process of antigen presentation

  • DNA Replication
  • Active Transport
  • Cellular Receptors
  • Endocytosis and Exocytosis
  • Enzyme Inhibition
  • Enzyme Kinetics
  • Protein Structure
  • Transcription of DNA
  • Translation of DNA
  • Anaerobic Respiration
  • Electron Transport Chain
  • Gluconeogenesis
  • Calcium Regulation
  • External Balance of Potassium
  • Internal Balance of Potassium
  • Sodium Regulation
  • Cell Membrane
  • Endoplasmic Reticulum
  • Golgi Apparatus
  • Mitochondria
  • Blood Vessels
  • Cellular Adaptations
  • Epithelial Cells
  • Muscle Histology
  • Structure of Glands
  • Control of Stroke Volume
  • Control of Heart Rate
  • Cardiac Cycle
  • Cardiac Pacemaker Cells
  • Conduction System
  • Contraction of Cardiac Muscle
  • Ventricular Action Potentials
  • Control of Blood Pressure
  • Capillary Exchange
  • Flow Within The Cardiovascular System
  • Regulation of Peripheral Blood Flow
  • Venous Return
  • Cardiac Muscle
  • Hepatic Circulation
  • Skeletal Muscle
  • Airway Resistance
  • Lung Volumes
  • Mechanics of Breathing
  • Gas Exchange
  • Oxygen Transport in The Blood
  • Transport of Carbon Dioxide in the Blood
  • Ventilation-Perfusion Matching
  • Chemoreceptors
  • Cough Reflex
  • Neural Control of Ventilation
  • Respiratory Regulation of Acid-Base Balance
  • Responses of The Respiratory System to Stress
  • Regulation of Saliva
  • Secretion of Saliva
  • Gastric Acid Production
  • Gastric Mucus Production
  • Digestion and Absorption
  • Histology and Cellular Function of the Small Intestine
  • Absorption in the Large Intestine
  • Large Intestinal Motility
  • Bilirubin Metabolism
  • Carbohydrate Metabolism in the Liver
  • Lipid Metabolism in the Liver
  • Protein and Ammonia Metabolism in the Liver
  • Storage Functions of the Liver
  • Bile Production
  • Function of The Spleen
  • Exocrine Pancreas
  • Somatostatin
  • Proximal Convoluted Tubule
  • Loop of Henle
  • Distal Convoluted Tubule and Collecting Duct
  • Storage Phase of Micturition
  • Voiding Phase of Micturition
  • Antidiuretic Hormone
  • Renin-Angiotensin-Aldosterone System
  • Urinary Regulation of Acid-Base Balance
  • Water Filtration and Reabsorption
  • Development of the Reproductive System
  • Gametogenesis
  • Gonadotropins and the Hypothalamic Pituitary Axis
  • Menstrual Cycle
  • Placental Development
  • Fetal Circulation
  • Maternal Adaptations in Pregnancy
  • Cells of the Nervous System
  • Central Nervous System
  • Cerebrospinal Fluid
  • Neurotransmitters
  • Peripheral Nervous System
  • Action Potential
  • Excitatory and Inhibitory Synaptic Signalling
  • Resting Membrane Potential
  • Synaptic Plasticity
  • Synaptic Transmission
  • Ascending Tracts
  • Auditory Pathway
  • Consciousness and Sleep
  • Modalities of Sensation
  • Pain Pathways
  • Sensory Acuity
  • Visual Pathway
  • Descending Tracts
  • Lower Motor Neurones
  • Muscle Stretch Reflex
  • Upper Motor Neurones
  • Aqueous Humour
  • Ocular Accommodation
  • Thyroid Gland
  • Parathyroid Glands
  • Adrenal Medulla
  • Zona Glomerulosa
  • Zona Fasciculata
  • Zona Reticularis
  • Endocrine Pancreas
  • The Hypothalamus
  • Anterior Pituitary
  • Posterior Pituitary
  • White Blood Cells – Summary
  • Barriers to Infection
  • Infection Recognition Molecules
  • Phagocytosis
  • The Complement System

Antigen Processing and Presentation

  • Primary and Secondary Immune Responses
  • T Cell Memory
  • Acute Inflammation
  • Autoimmunity
  • Chronic Inflammation
  • Hypersensitivity Reactions
  • Immunodeficiency
  • Types of Immunity
  • Antibiotics
  • Viral Infection
  • Blood Groups
  • Coagulation
  • Erythropoiesis
  • Iron Metabolism
  • Mononuclear Phagocyte System

Original Author(s): Antonia Round Last updated: 17th July 2023 Revisions: 10

  • 1 Antigen Presentation
  • 2.1 MHC Class I Molecules
  • 2.2 MCH Class II Molecules
  • 3.1 T Cell Receptors
  • 3.2 Co-Receptors
  • 4 Clinical Relevance – Autoimmune disease

T cells can only recognise antigens when they are displayed on cell surfaces. This is carried out by  Antigen-presenting cells (APCs) , the most important of which are dendritic cells, B cells, and macrophages. APCs can digest proteins they encounter and display peptide fragments from them on their surfaces for other immune cells to recognise.

This process of antigen presentation allows T cells to “see” what proteins are present in the body and to form an adaptive immune response against them. In this article, we shall discuss antigen processing, presentation, and recognition by T cells.

Antigen Presentation

Antigens are delivered to the surface of APCs by Major Histocompatibility Complex (MHC) molecules. Different MHC molecules can bind different peptides. The MHC is highly polygenic and polymorphic which equips us to recognise a vast array of different antigens we might encounter. There are different classes of MHC, which have different functions:

  • MHC class I  molecules are found on all nucleated cells (not just professional APCs) and typically present intracellular antigens such as viruses.
  • MHC class II molecules are only found on APCs and typically present extracellular antigens such as bacteria.

This is logical because should a virus be inside a cell of any type, the immune system needs to be able to respond to it. This also explains why pathogens inside human red blood cells (which are non-nucleated) can be difficult for the immune system to find, such as in malaria.

Whilst this is the general rule, in cross-presentation extracellular antigens can be presented by MHC class I, and in autophagy intracellular antigens can be presented by MHC class II.

Antigen Processing

Before an antigen can be presented, it must first be processed . Processing transforms proteins into antigenic peptides.

MHC Class I Molecules

Intracellular peptides for MHC class I presentation are made by proteases and the proteasome in the cytosol, then transported into the endoplasmic reticulum via TAP (Transporter associated with Antigen Processing) to be further processed.

They are then assembled together with MHC I molecules and travel to the cell surface ready for presentation.

process of antigen presentation

Fig 1 – Diagram demonstrating the production of peptides for MHC class I presentation

MCH Class II Molecules

The route of processing for exogenous antigens for MHC class II presentation begins with endocytosis of the antigen. Once inside the cell, they are encased within endosomes that acidify and activate proteases, to degrade the antigen.

MHC class II molecules are transported into endocytic vesicles where they bind peptide antigen and then travel to the cell surface.

process of antigen presentation

Fig 2 – Diagram showing processing of antigens for MHC Class II presentation by a dendritic cell

The antigen presented on MHCs is recognised by T cells using a T cell receptor (TCR) . These are  antigen-specific .

T Cell Receptors

Each T cell has thousands of TCRs , each with a unique specificity that collectively allows our immune system to recognise a wide array of antigens.

This diversity in TCRs is achieved through a process called V(D)J recombination during development in the thymus. TCR chains have a variable region where gene segments are randomly rearranged, using the proteins RAG1 and RAG2 to initiate cleavage and non-homologous end joining to rejoin the chains.

The diversity of the TCRs can be further increased by inserting or deleting nucleotides at the junctions of gene segments; together forming the potential to create up to 10 15 unique TCRs.

TCRs are specific not only for a particular antigen but also for a specific MHC molecule. T cells will only recognise an antigen if a specific antigen with a specific MHC molecule is present: this phenomenon is called  MHC restriction .

Co-Receptors

As well as the TCR, another T cell molecule is required for antigen recognition and is known as a co-receptor. These are either a CD4 or CD8 molecule:

  • CD4 is present on T helper cells and only binds to antigen-MHC II complexes.
  • CD8 is present on cytotoxic T cells and only binds to antigen-MHC I complexes.

This, therefore, leads to very different effects. Antigens presented with MHC II will activate T helper cells and antigens presented with MHC I activate cytotoxic T cells. Cytotoxic T cells will kill the cells that they recognise, whereas T helper cells have a broader range of effects on the presenting cell such as activation to produce antibodies (in the case of B cells) or activation of macrophages to kill their intracellular pathogens.

Clinical Relevance – Autoimmune disease

It is important to note that APCs may deliver foreign antigens or self-antigens. In the case of autoimmune diseases, self-antigens are presented to T cells, which then initiates an immune response against our own tissues.

For example, in Graves’ disease , TSHR (thyroid stimulating hormone receptor) acts as a self-antigen and is presented to T cells. This then activates B cells to produce autoantibodies against TSHRs in the thyroid. This results in the activation of TSHRs leading to hyperthyroidism and a possible goitre.

[start-clinical]

Clinical Relevance - Autoimmune disease

[end-clinical]

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Genetics of antigen processing and presentation

Adrian kelly.

Department of Pathology, University of Cambridge, Cambridge, CB21QP UK

John Trowsdale

Immune response to disease requires coordinated expression of an army of molecules. The highly polymorphic MHC class I and class II molecules are key to control of specificity of antigen presentation. Processing of the antigen, to peptides or other moieties, requires other sets of molecules. For classical class I, this includes TAP peptide transporters, proteasome components and Tapasin, genes which are encoded within the MHC. Similarly, HLA-DO and -DM, which influence presentation by HLA class II molecules, are encoded in the MHC region. Analysis of MHC mutants, including point mutations and large deletions, has been central to understanding the roles of these genes. Mouse genetics has also played a major role. Many other genes have been identified including those controlling expression of HLA class I and class II at the transcriptional level. Another genetic approach that has provided insight has been the analysis of microorganisms, including viruses and bacteria that escape immune recognition by blocking these antigen processing and presentation pathways. Here, we provide a brief history of the genetic approaches, both traditional and modern, that have been used in the quest to understand antigen processing and presentation.

Some history

The early history of the genetics of antigen processing and presentation followed from the work on histocompatibility in mice, initially by Peter Gorer, who worked at the Lister Institute and Guy’s hospital in London. His discovery of the MHC in turn was inspired by three developments. First was the curious pastime of inbreeding mouse strains, a fashionable hobby which spread from China. It reached America in the early 1900s, and after a while, pioneering geneticists realised the advantage of inbred strains for research. Many of the mouse strains were started over 100 years ago. C57BL, one of the original strains, was designated as the mice were black and were number 57. BALB/c mice were white, on the other hand, and were designated by their originator, Halsey J. Bagg, as Bagg albino, or BALB/c for short. A fascinating early history of these developments is presented in a book on the natural history of the MHC (Klein 1986 ).

Inbred strains were pivotal in the next development, where researchers used them to study the genetics of tumour rejection. As early as 1903, it was discovered that tumours that grew well when transferred within the same strain were rejected in a different one. Then, in 1922, Little and Johnson showed that transplantation of normal tissue was subject to the same strain specificity as tumours. A third stimulus was the development of blood group research, largely attributed to Landsteiner.

JB Haldane suggested that tumour resistance factors may be akin to blood group antigens, but it was Gorer who performed experiments to test the idea that antigens were shared by both malignant and normal tissues. This led to the formulation of an immunological theory of transplantation, which was later systematised by Peter Medawar. George Snell was studying similar phenomena, and after collaborating with Gorer, he proposed calling the tumour-resistance factors Histocompatibility genes. His approach started to reveal some of the complexity of histocompatibility.

Early work leading to the discovery of the human HLA complex developed in the 1950s and was dependent on the study of antibodies against alloantigens on white blood cells by three laboratories: Jean Dausset in Paris, Rose Payne and Walter Bodmer in Stanford, and Jon van Rood in Leiden. It was realised that some patients, and women who had borne several children, tended to make such antibodies, which were independent of ABO blood groups and erythrocytes. At the time, human organ transplantation was becoming widespread, and it gradually became accepted that human leukocyte antigens were the equivalent of mouse H-2 antigens. The hope was that careful matching, as in ABO, could lead to organ transplants that were not rejected. It was soon realised that the HLA system was more complex than ABO and progress depended on exchange of cells and antisera. The International Histocompatibility Workshops , which have been held every few years since 1964, were critical in interpreting and integrating information obtained with a variety of techniques from different laboratories. Analysis of data from these workshops indicated that a single genetic region was pivotal, namely, in humans, HLA, the Major Histocompatibility Complex. An associated protein chain, β2microglobulin, was identified as a component of HLA antigens and was later mapped outside the complex to chromosome 15 (Goodfellow et al. 1975 ).

Attempts to develop in vitro assays to study graft rejection led to the mixed lymphocyte reaction (MLR), which also turned out to be controlled by the MHC region. However, the results did not correlate completely with the serologically defined determinants. Work in both human and mouse indicated that these determinants, as well as MLR responsiveness, were both part of the H2 and HLA complexes but were separated genetically. Meanwhile, a different set of experiments showed that levels of antibody response to short synthetic polypeptides were controlled by the MHC. For example, C57 mice responded well to the branched synthetic polypeptide (T, G)-A-L, but CBA animals were poor responders. These effects were traced to the H-2 region leading to the so-called immune response (Ir) genes (Benacerraf and McDevitt 1972 ).

These many years of work, all indicated that the MHC was a major hub controlling a number of immunological phenomena. Indeed, additional experiments showed that the MHC also controlled susceptibility to viruses. Work in Canberra showed that cytotoxic T cells simultaneously recognised viral antigens and MHC molecules, in a phenomenon that came to be known as MHC restriction (Zinkernagel and Doherty 1974 ).

The nature of the MHC became even more complex when it was proposed that T cell suppression was also controlled by the class II region (Green et al. 1983 ). There followed a decade of controversy over the existence of this phenomenon (Bloom et al. 1992 ). It was eventually accepted, and the responsible T cells were called regulatory to distinguish them from the confusing history of suppression (Sakaguchi et al. 2007 ). The genetics behind the controversy concerned the I-J gene which was supposed to map to the I region of the mouse MHC and control the function of suppressor T cells. The I-J antigens were proposed to be soluble molecules secreted by suppressor T cells. It was a shock to find that discrete I-J genes did not exist once the I region of the mouse had been cloned (Kronenberg et al. 1983 ).

The genetics of antigen processing and presentation was advanced dramatically in the late 1980s when two further major technical developments helped to get to grips with the complexity. One was the DNA cloning revolution and the second was the determination of the structure of MHC molecules from crystals. Initial cloning of H-2 and HLA antigen genes led quickly to assembly of maps of the MHC in humans and mice. These dramatically simplified the picture to just a handful of class I and class II loci, albeit with a profound level of polymorphism. The early maps of mouse MHC were painstakingly assembled from overlapping cosmids (Steinmetz and Hood 1983 ). Many different human haplotypes have been analysed by these techniques (Horton et al. 2008 ; Shiina et al. 2004 ), as well as using more modern, high-throughput approaches (Norman et al. 2016 ).

The nature of the polymorphism was mysterious, as class I and class II chains encompassed many amino acid changes seemingly scattered throughout the first two domains of class I and the first domains of both chains of class II. The breakthrough came with the crystal structure of the first MHC antigen, HLA-A2 by Pamela Bjorkman, who was a PhD student at the time in the Wiley/Strominger laboratories (Bjorkman et al. 1987a , Bjorkman et al. 1987b ). The realisation that class I and class II molecules possessed a groove which bound peptides immediately swept away other models of antigen recognition, such as those invoking independent receptors for antigen and histocompatibility molecules on T cells.

The development of molecular immunology through the creation of mutants, DNA sequencing, protein structure and gene discovery then paved the way for uncovering the various components of the antigen processing and presentation pathways, as outlined below (Table ​ (Table1 1 ).

Some human antigen processing and presenting components. Alternative names and gene designations are given in parentheses

Mutant cell lines

Panels of HLA homozygous typing cell lines have been important tools in the analysis of human tissue types through HLA classes I and II. These lines were derived by Epstein Barr Virus transformation of lymphoid cells from consanguineous mating, usually first cousin. They have been used for over 40 years by the HLA community and are still in use today (Turner et al. 2018 ).

Analysis of the involvement of the HLA region in antigen processing and presentation was further enhanced by the generation of deletions and other mutations in lymphoblastoid cell lines (Fig. ​ (Fig.1). 1 ). One series of mutants was made by γ ray mutagenesis of the cell line B-LCL721 by the DeMars group (DeMars et al. 1984 ; Kavathas et al. 1980 ). Cells were subjected to 2 cycles of mutagenesis followed by immune-selection with monoclonal antibodies for MHC antigen loss. B-LCL721 contains the following two MHC haplotypes:

  • HLA-A*01 HLA-B*08 HLA-DRB1*03 HLA-DPB1*04
  • HLA-A*02 HLA-B*51 HLA-DRB1*01 HLA-DPB1*02

An external file that holds a picture, illustration, etc.
Object name is 251_2018_1082_Fig1_HTML.jpg

Composition of the mutant lines derived in the DeMars laboratory (DeMars et al. 1984 ; Kavathas et al. 1980 ) and the further derivative T2 (Salter et al. 1985 ). The shaded boxes show the proposed extents of the deletions. See text for more details of typing. These mutant cells have been used in numerous antigen processing and presentation studies. The Figure adapted from Demars et al. 1984

More details on the class I HLA types are available on the IPD-IMGT/HLA database. 1 To our knowledge, not all class II genes have been typed in these cells. Mutant cell lines were isolated by subjecting these cells to irradiation. After 5 days growth, the survivors were selected with complement and a variety of monoclonal antibodies. Analysis of these mutants showed that they contained large homozygous or hemizygous deletions over the MHC region (Fig.  1 ). One such line LCL721.174, and its derivative 174xCEM.T2, has been used extensively to investigate TAP transporter function and MHC class I peptide loading. 174xCEM.T2, more commonly referred to as T2, was generated by fusing LCL721.174 with CEMR.3, a T-LCL, and selecting for loss of CEMR.3-derived copies of chromosome 6 (Salter et al. 1985 ). Both 174XCEM.T2 and LCL721.174 therefore carry the same chromosome 6 MHC deletion.

A similar procedure was used by Andreas Ziegler, using the lymphoma cell line BJAB.B95.8.6 (Spring et al. 1985 ). The wild-type cells were typed with the resolution available at that time as:

  • HLA-A*1 HLA-B*35 HLA-C*4 HLA-DR*5 HLA-DQw3 HLA-DP*4
  • HLA-A*2 HLA-B*13 HLA-C* HLA-DR* HLA-DQw1 HLA-DP*2

The Pious laboratory used a variation of this approach to isolate mutants in class II (8.1.6 and 9.28.6) by mutagenizing with EMS an HLA-DR3+ cell line, T5-1 (Mellins et al. 1988 ; Pious et al. 1985 ). Similarly, in mouse studies designed to investigate the nature of self and non-self-recognition, Klaus Karre generated a murine cell line RMA-S that lacked surface H-2 expression but was rejected in tumour transplant models (Karre et al. 1986 ). Analysis of this cell line was instrumental in providing early models for peptide loading by MHC class I molecules (Townsend et al. 1989 ). In addition, Roberto Accolla irradiated Raji cells to produce a mutant line RJ2.2.5 selecting against HLA-DR expression with an antibody D1–12(Accolla 1983 ), facilitating identification of CIITA.

These mutant cell lines and their derivatives have been instrumental in a long series of experimental approaches to uncover various components of antigen processing, and they continue to be important tools in investigating their mechanism of action.

TAP transporters

A key insight into antigen processing was the finding that influenza A-specific cytotoxic T lymphocytes (CTL) recognise discrete epitopes of the nucleoprotein molecule. These data implied a mechanism for generation of viral protein fragments and their transport to the cell surface for presentation to CTL (Townsend et al. 1985 ). The peptide-binding groove in HLA molecules was a strong contender for the peptide carrier. There was a problem though in that MHC molecules were integrated into the cell membrane, so how did peptide fragments, which lacked signal sequences, access the endoplasmic reticulum (ER) to be loaded? How were the peptides transported to the cell surface on MHC molecules?

The solution came from MHC mapping and analysis of the mutants referred to above. Several groups simultaneously identified genes encoding transporter molecules mapping to the MHC. These were transporters of the so-called ABC (ATP-binding cassette) type, which were subsequently named TAP, for Transporters Associated with Antigen Processing (Deverson et al. 1990 ; Monaco et al. 1990 ; Spies et al. 1990 ; Trowsdale et al. 1990 ). These data suggested immediately that the transporters, encoded as a heterodimer of two proteins, TAP1 and TAP2, were responsible for pumping peptides into the ER (Kelly et al. 1992 ). To confirm this, the TAP1 sequence restored HLA class I expression when transfected into a cell line with a mutant TAP1 gene, LCL721.134 (Spies and DeMars 1991 ), and the TAP2 sequence restored function and co-precipitation of TAP1 and TAP2 when transfected into cells deficient in TAP2 (Kelly et al. 1992 ). However, this was not the case when using LCL721.174 cells, which maintained a large deletion over the class II region, covering both components of the heterodimer, TAP1 and TAP2(Spies and DeMars 1991 ). Studies of rats and chickens were particularly informative as the TAP genes are polymorphic in these species. It turned out that specific allelic versions of TAP supply peptides appropriate for class I molecules whose genes are linked in cis on the haplotype. Inappropriate pairing of TAP alleles with class I alleles they serve with non-binding peptides led to reduced expression of class I, which could be detected at the cell surface (Deverson et al. 1990 ; Kaufman 2015 ; Powis et al. 1996 ).

Natural mutants in TAP

A number of individuals have been identified with immune-deficiencies due to mutations in TAP (de la Salle et al. 1994 ; Zimmer et al. 2005 ). These belong to the category of type I bare lymphocyte (BLS) syndrome, where HLA class I, but not class II, is affected. These patients generally have a severe reduction of class I at the cell surface, but in spite of this, most of these individuals reach adulthood. They are rare and are almost exclusively HLA homozygous due to first cousin parentage. They generally display chronic infections of the respiratory tract (purulent rhinitis, pansinusitis, otitis media) with bacteria ( H. influenzae , S. pneumoniae , S. aureus , K. pneumoniae , E. coli and P. aeruginosa ). About half of them exhibit granulomatous skin lesions. This may be due to suboptimal cytokine and cellular responses, leading to tissue damage and favouring subsequent bacterial infection and further recruitment of phagocytic cells. Indeed, antibiotics that impair neutrophils appear to be beneficial.

Patients with defects in TAP do not suffer from severe viral infection. This is unexpected but may relate to the fact that they have a normal humoral (antibody) response and significant numbers of T cells, particularly γδT cells, as well as NK cells and neutrophils. Additionally, presentation of some viral antigens is TAP-independent. Another symptom in these patients is necrotizing granulomatous lesions particularly around the nose, resulting in loss of the septum and associated cartilage. Presentation is variable though. The skin ulcers were found to contain macrophages and NK cells.

In terms of biological effects, the proportion of T cells may be reduced in patients with TAP defects, but there is wide variation in phenotype. They tend to have a higher proportion of γδT cells. Interestingly, numbers of NK cells are normal, but they have no cytotoxic activity against the standard class I-negative targets, unless activated by cytokines.

Proteasome components—LMPs

At the same time that TAPs were discovered, clues to the proteolytic machinery, responsible for breaking the antigenic proteins into peptides, were also provided, by studying mutants over the MHC region. The biochemical prelude to this discovery came in the early 1980s when Monaco and McDevitt described a series of up to16 low-molecular weight proteins , LMPs, that mapped to the MHC. Initially, the functions of these proteins were not obvious, but they formed a complex by co-precipitation and varied between different mouse haplotypes, in other words were polymorphic (Monaco and McDevitt 1984 ). It was subsequently established that genes for two interferon-inducible, catalytic proteasome subunits, LMP2 (PSMB9; β1i) and LMP7 (PSMB8: β5i), were closely linked to the TAP1 and TAP2 genes in both human and mouse MHC (Glynne et al. 1991 ; Kelly et al. 1991a ). As with the TAPs, finding proteasome components encoded in the MHC immediately suggested that the proteasome was responsible for producing the antigenic peptides. Proteasomes are ubiquitous cellular components responsible for continual turnover of proteins in general. However, the MHC-encoded proteasome genes were interferon inducible and, when expressed, replaced constitutive components in a subset of the main structures. Another interferon-inducible subunit PSMB10 (β2i) is encoded outside the MHC on chromosome 16q22.1.

ERp57 and ERAP1

A number of chaperones are associated with class I as it matures and picks up peptide in the peptide-loading complex. These chaperones serve multiple proteins in the ER and are not dedicated to class I. However, ERp57 is a component of the peptide-loading complex. The protein aids folding of nascent glycoproteins by facilitating disulphide bond isomerisation.

ERAP1 is an amino peptidase. It plays a role in determining the length and sequence of peptides bound and presented by class I allotypes. HLA-B27 is strongly associated with ankylosing spondylitis (Chen et al. 2014 ), and genetic studies indicated that certain ERAP1 allotypes are more associated with ankylosing spondylitis than others, due to their contribution to peptide trimming (Reeves et al. 2014a , Reeves et al. 2014b ). There has been some controversy over this effect as it was difficult to analyse genetically. It was proposed to involve specific combinations of different ERAP1 allotypes, making association studies difficult (Reeves et al. 2015 ; Robinson and Brown 2015 ).

The gene for Tapasin, another component of the antigen processing machinery, is located just outside the MHC region (Ortmann et al. 1997 ). The product of this gene, which is an additional member of the immunoglobulin gene family, links the peptide transporter to the nascent class I molecule in a complex, the peptide-loading complex (Blees et al. 2017 ). Optimisation of the MHC class I peptide cargo is proposed to be dependent on Tapasin (Williams et al. 2002 ). However, class I molecules vary in their dependence on the protein, an effect that has been mapped to specific positions on the HLA molecule (Park et al. 2003 ) as well as to its conformational flexibility (Garstka et al. 2011 ). For example, the HLA-B*44 allele, which differs exclusively at position 156, B*44:02 (156Asp), is Tapasin-dependent, whereas other alleles are not (Badrinath et al. 2012 ). The reason for this is not known but could relate to the fact that some virus products compromise antigen presentation by interacting with the Tapasin protein.

There is evidence that the jawed vertebrate genome has undergone duplication at least twice in its evolutionary history, according to the 2R hypothesis. Accordingly, it was demonstrated that there are traces of at least four clusters of genes related to those in the MHC proper on chromosome 6 (Kasahara 1999 ). One paralogous region, identified by Louis Du Pasquier, was at chromosome position 12p13.3. A gene in this region shared sequence homology with Tapasin, dubbed TAPBPR (Teng et al. 2002 ). The product of this gene was subsequently shown to be a novel component of the MHC class I presentation pathway, which acts as a peptide exchange catalyst (Hermann et al. 2015 ; Neerincx and Boyle 2017 ). TAPBPR interacts with class I in a similar manner to Tapasin but is not complexed to TAP (Jiang et al. 2017 ). TAPBPR links UDP-glucose:glycoprotein glucosyltransferase 1 onto MHC class I (Neerincx et al. 2017 ). Tapasin is monomorphic, but TAPBPR is relatively polymorphic and there are a number of common alleles and splice variants in humans (Porter et al. 2014 ). The relationship between the products of these alleles and MHC Class I loci and alleles is not known. As with Tapasin, it appears that some alleles of class I are dependent, and others independent, of the molecule.

HLA-DM and DO

The existence of an MHC-encoded factor that was essential for MHC class II antigen presentation was first suggested through the characterisation of mutagenised B lymphoblastoid cells selected for loss of HLA-DR3 reactivity with a DR3-specific antibody, 16:23(Mellins et al. 1990 ). These cells had normal levels of cell surface DR but were unable to present native antigen to T cells. They possessed class II molecules that were predominantly filled with the CLIP peptide and fell apart in the presence of SDS. The defect was eventually mapped to HLA-DM (Morris et al. 1994 ), a class II-related molecule previously identified in both mouse and human in screens for expressed genes encoded on cosmids spanning the MHC region (Kelly et al. 1991b ; Cho et al. 1991 ). HLA-DM acts as a peptide editing chaperone stabilising class II whilst exchanging CLIP for antigenic peptide. DM activity is regulated by a second non-classical class II molecule, now called HLA-DO. HLA-DO alpha and beta chains were first identified due to their high homology with human and murine classical class II molecules (Larhammar et al. 1985 ; Tonnelle et al. 1985 ; Trowsdale and Kelly 1985 ). It proved much harder to decipher the role of DO even though the molecule was identified some 6 years before DM. DOA and DOB were not located together in the MHC, and the chains showed different mRNA expression patterns initially suggesting that they would not associate as a pair. DO resides in late endosomal compartments but requires association with DM in the endoplasmic reticulum for correct assembly (Liljedahl et al. 1996 ). The in vivo role of DO is still debatable, but mechanistically, it functions as a negative regulator of DM activity (van Ham et al. 1997 ; Denzin et al. 1997 ). Unlike the transient interactions seen between DM and DR, the DM/DO interaction is very stable, suggesting that DO acts as a competitive inhibitor of DM, a view consistent with the DM/DO crystal structure (Guce et al. 2013 ).

Haplotypes and linkage disequilibrium

It has been known for some time that the MHC comprises a large region in linkage disequilibrium (LD), or polymorphic frozen blocks (Dawkins et al. 1999 ). In some populations, for example, combinations of alleles, such as HLA-A1-B8-DR3, are more commonly found together than would be expected based on frequencies of individual alleles in the population. Several mechanisms may be invoked to explain this. First, there may have been insufficient time for recombination after relatively recent expansion of families, in some cases in isolated populations. Another possibility is that recombination ‘cold spots’ in the MHC sequence restrain the level of exchange of alleles between haplotypes. This may be facilitated by a reduced level of pairing at meiosis in a region such as the MHC, where the variation between haplotypes compromises homologous interaction. Indeed, overall recombination is low in the MHC.

An attractive explanation for the high LD is clustering of alleles that encode proteins that work well together and maintenance of functionally coordinated sets of alleles. As discussed above, the discovery of both TAP transporters and LMP proteasome components mapping to the MHC was largely serendipitous and was inspired to some extent by the notion that the MHC was a cluster of genes with inter-related functions. Furthermore, it was proposed that linkage of polymorphic transporters with polymorphic MHC class I genes permitted functional coordination, such that appropriate binding peptides, for the class I molecules linked in cis , were pumped by the relevant TAP. This turned out to be the case for rats and chickens, where genes for class I and TAP are in close proximity (Powis et al. 1992 ; Tregaskes et al. 2016 ). In the human MHC TAP transporters, genes are separated from the class I genes they serve by the class III region, so this functional integration may not be fully operational in our species. Another consideration is that each individual has two haplotypes, the various components of which must cooperate to some extent.

Recent data add weight to the notion of a high degree of allelic integration on individual haplotypes. It is becoming appreciated that, in addition to protein-coding loci, other polymorphic genomic features are embedded in the MHC complex. One clue to this came from the finding that a single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C associated with levels of mRNA transcript and cell-surface expression (Kulkarni et al. 2011 ). Binding of microRNA hsa-miR-148 to a variable 3′ untranslated region in HLA-C genes regulated their expression. The conclusion was that expression levels may be regulated both by cis- and trans- acting factors. A further indication of the integration along haplotypes came from data relating to the way that class I molecules ‘educate’ by interacting with receptors on NK cells. Hydrophobic leader sequences from class I molecules supply peptides that bind HLA-E, which instructs CD94/NKG2A receptors on NK cells. Leader sequences of HLA-B molecules are dimorphic: Those with − 21 methionine (− 21 M) provide peptides that bind HLA-E, whereas − 21 threonine do not. Those haplotypes with -21 M rarely encode the ligands for other NK receptors, namely Bw4+ HLA-B and C2+ HLA-C. From these data, it was proposed that there are two schools of HLA haplotypes; one focused on supplying CD94/NKG2A ligands, and the other, KIR ligands. Individuals with − 21 M had NKG2A+ cells that were more effective than those with only − 21 T (Horowitz et al. 2016 ). Similarly, HLA-A leader sequences determine expression levels of HLA-E, again influencing interaction with CD94/NKG2A on NK cells and in turn HIV replication (Ramsuran et al. 2018 ).

Regulation of transcription and translation

Analysis of mutants has also been productive for identifying regulators of antigen processing and presenting genes. For many years, it was difficult to track down a master regulator of class I. On the other hand, mutants affecting class II were isolated from bare lymphocyte patients (Reith and Mach 2001 ). The class II master regulator CIITA is a nucleotide-binding domain and leucine-rich repeat receptor (NLR) protein. This large gene was initially found by expression cloning in a class II-deficient cell line (Steimle et al. 1993 ). Mutants invoking loss of function of CIITA generally result in severe immunodeficiency, a form of bare lymphocyte syndrome. Individuals with BLS have impaired antibody and T cell responses due to the lack of MHC class II expression. Class II transcription requires, in addition to CIITA, at least three additional factors: RFX5, RFX-AP and RFX-ANK. The genes encoding these factors were identified by comparing panels of rare BLS patients and mutant cell lines selected for loss of class II expression. This identified four complementation groups. Transient heterokaryon fusions between these cell lines restored class II expression if the partners harboured defects in different components, thereby defining the four groups. A combination of genetic complementation and protein characterisation eventually identified the genetic lesions, as reviewed in Reith and Mach ( 2001 ).

It was only in the last decade that a master transcription regulator for class I was discovered (Kobayashi and Elsen, 2012 ; Meissner et al. 2010 ; Neerincx et al. 2013 ). Like the class II transcription activator, CIITA, NLRC5 is an NLR protein and the two molecules share some homology. In cell lines defective in class I expression, such as mouse melanoma B16F10, over-expressed NLRC5 could restore class I expression. In human cells, over-expression of NLRC5 resulted in induction of non-classical class I genes HLA-E, -F and -G, which normally exhibit a restricted tissue expression. CIITA-dependent activation of HLA class II requires the enhanceosome complex, which binds to a motif, SXY, in the promoter of the gene. NLRCF probably interacts with a similar module upstream of class I genes.

Confirmation of the role of NLRC5 in regulation of MHC class I was provided by studying Nlrc5 -deficient knock-out mice (Staehli et al. 2012 ). The data showed that MHC class I was downregulated, exhibiting the greatest effect in cells in the immune system. However, treatment of these mice with inflammatory stimuli, such as interferon or LPS, resulted in significant class I expression, indicating that Nlrc5 -independent mechanisms must exist to regulate MHC class I.

Recent work suggests that there is still more to learn about variation in HLA expression. For example, the Anderson laboratory identified an elaborate system regulating forms of HLA-C, which is specific to natural killer cells, and could relate to NK cell licencing or education (Li et al. 2018 ). Other work suggests that, in addition to allelic differences, levels of class I should be taken into account in relation to autoimmunity, infection and transplantation (Apps et al. 2013 ; Kaur et al. 2017 ; Li et al. 2018 ; Petersdorf et al. 2014 ).

Screening for novel components

New screening techniques have the potential to identify novel factors involved in MHC biology. For example, forward genetic screens involving retroviral insertional mutagenesis or random CRISPR/Cas9 targeting of a haploid human cell line KBM7 implicate TXNDC11 as a novel factor required for MHC class I endoplasmic reticulum-associated protein degradation (ERAD) (Timms et al. 2016 ). In addition, a genome-wide RNAi screen was used to identify pathways regulating MHC class II antigen presentation (Paul et al. 2011 ).

Immunogenetics has played a predominant role in uncovering many of the fundamentals of antigen processing and presentation. In this review, we have sketched out some of the history and background to the genetics, focussing mainly on the human system. Other contributions to this volume of Immunogenetics may be consulted for more in-depth coverage of individual components of antigen processing and presentation.

Funding information

JT is supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 695551).

1 https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/fetch_cell.cgi?10972

This article is part of the Topical Collection on Biology and Evolution of Antigen Presentation

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Module 20: The Immune System

Antigen-presenting cells, learning outcomes.

  • Describe the structure and function of antigen-presenting cells

Unlike NK cells of the innate immune system, B cells (B lymphocytes) are a type of white blood cell that gives rise to antibodies, whereas T cells (T lymphocytes) are a type of white blood cell that plays an important role in the immune response. T cells are a key component in the cell-mediated response—the specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria. There are three types of T cells: cytotoxic, helper, and suppressor T cells. Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, and helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and B cells when needed, and thus prevent the immune response from becoming too intense.

An antigen is a foreign or “non-self” macromolecule that reacts with cells of the immune system. Not all antigens will provoke a response. For instance, individuals produce innumerable “self” antigens and are constantly exposed to harmless foreign antigens, such as food proteins, pollen, or dust components. The suppression of immune responses to harmless macromolecules is highly regulated and typically prevents processes that could be damaging to the host, known as tolerance.

The innate immune system contains cells that detect potentially harmful antigens, and then inform the adaptive immune response about the presence of these antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.

After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class I or MHC class II molecules and are transported to the cell surface for antigen presentation, as illustrated in Figure 1. Note that T lymphocytes cannot properly respond to the antigen unless it is processed and embedded in an MHC II molecule. APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond. Helper T- cells are one of the main lymphocytes that respond to antigen-presenting cells. Recall that all other nucleated cells of the body expressed MHC I molecules, which signal “healthy” or “normal.”

Illustration shows a bacterium being engulfed by a macrophage. Lysosomes fuse with the vacuole containing the bacteria. The bacterium is digested. Antigens from the bacterium are attached to a MHC II molecule and presented on the cell surface.

Figure 1. An APC, such as a macrophage, engulfs and digests a foreign bacterium. An antigen from the bacterium is presented on the cell surface in conjunction with an MHC II molecule Lymphocytes of the adaptive immune response interact with antigen-embedded MHC II molecules to mature into functional immune cells.

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Antigen processing and presentation is the process by which protein antigen is ingested by an antigen-presenting cell (APC), partially digested into peptide fragments and then displayed on the surface of the APC associated with an antigen-presenting molecule such as MHC class I or MHC class II, for recognition by certain lymphocytes such as T cells.

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process of antigen presentation

  • 18.2 Major Histocompatibility Complexes and Antigen-Presenting Cells
  • Introduction
  • 1.1 What Our Ancestors Knew
  • 1.2 A Systematic Approach
  • 1.3 Types of Microorganisms
  • Multiple Choice
  • Fill in the Blank
  • Short Answer
  • Critical Thinking
  • 2.1 The Properties of Light
  • 2.2 Peering Into the Invisible World
  • 2.3 Instruments of Microscopy
  • 2.4 Staining Microscopic Specimens
  • 3.1 Spontaneous Generation
  • 3.2 Foundations of Modern Cell Theory
  • 3.3 Unique Characteristics of Prokaryotic Cells
  • 3.4 Unique Characteristics of Eukaryotic Cells
  • 4.1 Prokaryote Habitats, Relationships, and Microbiomes
  • 4.2 Proteobacteria
  • 4.3 Nonproteobacteria Gram-Negative Bacteria and Phototrophic Bacteria
  • 4.4 Gram-Positive Bacteria
  • 4.5 Deeply Branching Bacteria
  • 4.6 Archaea
  • 5.1 Unicellular Eukaryotic Parasites
  • 5.2 Parasitic Helminths
  • 5.5 Lichens
  • 6.1 Viruses
  • 6.2 The Viral Life Cycle
  • 6.3 Isolation, Culture, and Identification of Viruses
  • 6.4 Viroids, Virusoids, and Prions
  • 7.1 Organic Molecules
  • 7.2 Carbohydrates
  • 7.4 Proteins
  • 7.5 Using Biochemistry to Identify Microorganisms
  • 8.1 Energy, Matter, and Enzymes
  • 8.2 Catabolism of Carbohydrates
  • 8.3 Cellular Respiration
  • 8.4 Fermentation
  • 8.5 Catabolism of Lipids and Proteins
  • 8.6 Photosynthesis
  • 8.7 Biogeochemical Cycles
  • 9.1 How Microbes Grow
  • 9.2 Oxygen Requirements for Microbial Growth
  • 9.3 The Effects of pH on Microbial Growth
  • 9.4 Temperature and Microbial Growth
  • 9.5 Other Environmental Conditions that Affect Growth
  • 9.6 Media Used for Bacterial Growth
  • 10.1 Using Microbiology to Discover the Secrets of Life
  • 10.2 Structure and Function of DNA
  • 10.3 Structure and Function of RNA
  • 10.4 Structure and Function of Cellular Genomes
  • 11.1 The Functions of Genetic Material
  • 11.2 DNA Replication
  • 11.3 RNA Transcription
  • 11.4 Protein Synthesis (Translation)
  • 11.5 Mutations
  • 11.6 How Asexual Prokaryotes Achieve Genetic Diversity
  • 11.7 Gene Regulation: Operon Theory
  • 12.1 Microbes and the Tools of Genetic Engineering
  • 12.2 Visualizing and Characterizing DNA, RNA, and Protein
  • 12.3 Whole Genome Methods and Pharmaceutical Applications of Genetic Engineering
  • 12.4 Gene Therapy
  • 13.1 Controlling Microbial Growth
  • 13.2 Using Physical Methods to Control Microorganisms
  • 13.3 Using Chemicals to Control Microorganisms
  • 13.4 Testing the Effectiveness of Antiseptics and Disinfectants
  • 14.1 History of Chemotherapy and Antimicrobial Discovery
  • 14.2 Fundamentals of Antimicrobial Chemotherapy
  • 14.3 Mechanisms of Antibacterial Drugs
  • 14.4 Mechanisms of Other Antimicrobial Drugs
  • 14.5 Drug Resistance
  • 14.6 Testing the Effectiveness of Antimicrobials
  • 14.7 Current Strategies for Antimicrobial Discovery
  • 15.1 Characteristics of Infectious Disease
  • 15.2 How Pathogens Cause Disease
  • 15.3 Virulence Factors of Bacterial and Viral Pathogens
  • 15.4 Virulence Factors of Eukaryotic Pathogens
  • 16.1 The Language of Epidemiologists
  • 16.2 Tracking Infectious Diseases
  • 16.3 Modes of Disease Transmission
  • 16.4 Global Public Health
  • 17.1 Physical Defenses
  • 17.2 Chemical Defenses
  • 17.3 Cellular Defenses
  • 17.4 Pathogen Recognition and Phagocytosis
  • 17.5 Inflammation and Fever
  • 18.1 Overview of Specific Adaptive Immunity
  • 18.3 T Lymphocytes and Cellular Immunity
  • 18.4 B Lymphocytes and Humoral Immunity
  • 18.5 Vaccines
  • 19.1 Hypersensitivities
  • 19.2 Autoimmune Disorders
  • 19.3 Organ Transplantation and Rejection
  • 19.4 Immunodeficiency
  • 19.5 Cancer Immunobiology and Immunotherapy
  • 20.1 Polyclonal and Monoclonal Antibody Production
  • 20.2 Detecting Antigen-Antibody Complexes
  • 20.3 Agglutination Assays
  • 20.4 EIAs and ELISAs
  • 20.5 Fluorescent Antibody Techniques
  • 21.1 Anatomy and Normal Microbiota of the Skin and Eyes
  • 21.2 Bacterial Infections of the Skin and Eyes
  • 21.3 Viral Infections of the Skin and Eyes
  • 21.4 Mycoses of the Skin
  • 21.5 Protozoan and Helminthic Infections of the Skin and Eyes
  • 22.1 Anatomy and Normal Microbiota of the Respiratory Tract
  • 22.2 Bacterial Infections of the Respiratory Tract
  • 22.3 Viral Infections of the Respiratory Tract
  • 22.4 Respiratory Mycoses
  • 23.1 Anatomy and Normal Microbiota of the Urogenital Tract
  • 23.2 Bacterial Infections of the Urinary System
  • 23.3 Bacterial Infections of the Reproductive System
  • 23.4 Viral Infections of the Reproductive System
  • 23.5 Fungal Infections of the Reproductive System
  • 23.6 Protozoan Infections of the Urogenital System
  • 24.1 Anatomy and Normal Microbiota of the Digestive System
  • 24.2 Microbial Diseases of the Mouth and Oral Cavity
  • 24.3 Bacterial Infections of the Gastrointestinal Tract
  • 24.4 Viral Infections of the Gastrointestinal Tract
  • 24.5 Protozoan Infections of the Gastrointestinal Tract
  • 24.6 Helminthic Infections of the Gastrointestinal Tract
  • 25.1 Anatomy of the Circulatory and Lymphatic Systems
  • 25.2 Bacterial Infections of the Circulatory and Lymphatic Systems
  • 25.3 Viral Infections of the Circulatory and Lymphatic Systems
  • 25.4 Parasitic Infections of the Circulatory and Lymphatic Systems
  • 26.1 Anatomy of the Nervous System
  • 26.2 Bacterial Diseases of the Nervous System
  • 26.3 Acellular Diseases of the Nervous System
  • 26.4 Fungal and Parasitic Diseases of the Nervous System
  • A | Fundamentals of Physics and Chemistry Important to Microbiology
  • B | Mathematical Basics
  • C | Metabolic Pathways
  • D | Taxonomy of Clinically Relevant Microorganisms
  • E | Glossary

Learning Objectives

By the end of this section, you will be able to:

  • Identify cells that express MHC I and/or MHC II molecules and describe the structures and cellular location of MHC I and MHC II molecules
  • Identify the cells that are antigen-presenting cells
  • Describe the process of antigen processing and presentation with MHC I and MHC II

As discussed in Cellular Defenses , major histocompatibility complex (MHC) molecules are expressed on the surface of healthy cells, identifying them as normal and “self” to natural killer (NK) cells . MHC molecules also play an important role in the presentation of foreign antigens, which is a critical step in the activation of T cells and thus an important mechanism of the adaptive immune system.

Major Histocompatibility Complex Molecules

The major histocompatibility complex ( MHC ) is a collection of genes coding for MHC molecules found on the surface of all nucleated cells of the body. In humans, the MHC genes are also referred to as human leukocyte antigen (HLA) genes . Mature red blood cells , which lack a nucleus, are the only cells that do not express MHC molecules on their surface.

There are two classes of MHC molecules involved in adaptive immunity, MHC I and MHC II ( Figure 18.11 ). MHC I molecules are found on all nucleated cells; they present normal self-antigens as well as abnormal or nonself pathogens to the effector T cells involved in cellular immunity. In contrast, MHC II molecules are only found on macrophages , dendritic cells , and B cells ; they present abnormal or nonself pathogen antigens for the initial activation of T cells.

Both types of MHC molecules are transmembrane glycoproteins that assemble as dimers in the cytoplasmic membrane of cells, but their structures are quite different. MHC I molecules are composed of a longer α protein chain coupled with a smaller β 2 microglobulin protein, and only the α chain spans the cytoplasmic membrane. The α chain of the MHC I molecule folds into three separate domains: α 1 , α 2 and α 3 . MHC II molecules are composed of two protein chains (an α and a β chain) that are approximately similar in length. Both chains of the MHC II molecule possess portions that span the plasma membrane, and each chain folds into two separate domains: α 1 and α 2 , and β 1 , and β 2 . In order to present abnormal or non-self-antigens to T cells, MHC molecules have a cleft that serves as the antigen-binding site near the “top” (or outermost) portion of the MHC-I or MHC-II dimer. For MHC I, the antigen-binding cleft is formed by the α 1 and α 2 domains, whereas for MHC II, the cleft is formed by the α 1 and β 1 domains ( Figure 18.11 ).

Check Your Understanding

  • Compare the structures of the MHC I and MHC II molecules.

Antigen-Presenting Cells (APCs)

All nucleated cells in the body have mechanisms for processing and presenting antigens in association with MHC molecules. This signals the immune system, indicating whether the cell is normal and healthy or infected with an intracellular pathogen. However, only macrophages, dendritic cells, and B cells have the ability to present antigens specifically for the purpose of activating T cells; for this reason, these types of cells are sometimes referred to as antigen-presenting cells (APCs) .

While all APCs play a similar role in adaptive immunity, there are some important differences to consider. Macrophages and dendritic cells are phagocytes that ingest and kill pathogens that penetrate the first-line barriers (i.e., skin and mucous membranes). B cells, on the other hand, do not function as phagocytes but play a primary role in the production and secretion of antibodies. In addition, whereas macrophages and dendritic cells recognize pathogens through nonspecific receptor interactions (e.g., PAMPs , toll-like receptors , and receptors for opsonizing complement or antibody), B cells interact with foreign pathogens or their free antigens using antigen-specific immunoglobulin as receptors (monomeric IgD and IgM ). When the immunoglobulin receptors bind to an antigen, the B cell internalizes the antigen by endocytosis before processing and presentting the antigen to T cells.

Antigen Presentation with MHC II Molecules

MHC II molecules are only found on the surface of APCs. Macrophages and dendritic cells use similar mechanisms for processing and presentation of antigens and their epitopes in association with MHC II; B cells use somewhat different mechanisms that will be described further in B Lymphocytes and Humoral Immunity . For now, we will focus on the steps of the process as they pertain to dendritic cells.

After a dendritic cell recognizes and attaches to a pathogen cell, the pathogen is internalized by phagocytosis and is initially contained within a phagosome . Lysosomes containing antimicrobial enzymes and chemicals fuse with the phagosome to create a phagolysosome, where degradation of the pathogen for antigen processing begins. Proteases (protein-degrading) are especially important in antigen processing because only protein antigen epitopes are presented to T cells by MHC II ( Figure 18.12 ).

APCs do not present all possible epitopes to T cells; only a selection of the most antigenic or immunodominant epitopes are presented. The mechanism by which epitopes are selected for processing and presentation by an APC is complicated and not well understood; however, once the most antigenic, immunodominant epitopes have been processed, they associate within the antigen-binding cleft of MHC II molecules and are translocated to the cell surface of the dendritic cell for presentation to T cells.

  • What are the three kinds of APCs?
  • What role to MHC II molecules play in antigen presentation?
  • What is the role of antigen presentation in adaptive immunity?

Antigen Presentation with MHC I Molecules

MHC I molecules, found on all normal, healthy, nucleated cells , signal to the immune system that the cell is a normal “self” cell. In a healthy cell, proteins normally found in the cytoplasm are degraded by proteasomes (enzyme complexes responsible for degradation and processing of proteins) and processed into self-antigen epitopes ; these self-antigen epitopes bind within the MHC I antigen-binding cleft and are then presented on the cell surface. Immune cells, such as NK cells, recognize these self-antigens and do not target the cell for destruction. However, if a cell becomes infected with an intracellular pathogen (e.g., a virus), protein antigens specific to the pathogen are processed in the proteasomes and bind with MHC I molecules for presentation on the cell surface. This presentation of pathogen-specific antigens with MHC I signals that the infected cell must be targeted for destruction along with the pathogen.

Before elimination of infected cells can begin, APCs must first activate the T cells involved in cellular immunity. If an intracellular pathogen directly infects the cytoplasm of an APC, then the processing and presentation of antigens can occur as described (in proteasomes and on the cell surface with MHC I). However, if the intracellular pathogen does not directly infect APCs, an alternative strategy called cross-presentation is utilized. In cross-presentation, antigens are brought into the APC by mechanisms normally leading to presentation with MHC II (i.e., through phagocytosis), but the antigen is presented on an MHC I molecule for CD8 T cells. The exact mechanisms by which cross-presentation occur are not yet well understood, but it appears that cross-presentation is primarily a function of dendritic cells and not macrophages or B cells.

  • Compare and contrast antigen processing and presentation associated with MHC I and MHC II molecules.
  • What is cross-presentation, and when is it likely to occur?

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Microbiology Notes

Microbiology Notes

Antigen Processing, and Presentation – MHC Class I, Class II,

Table of Contents

What is Antigen Processing, And Presentation?

  • Antigen processing and presentation are essential steps in the immune response, particularly in the adaptive immune system. They involve the breakdown of antigens (foreign substances) into smaller fragments, their association with specialized proteins , and their subsequent presentation to immune cells known as T cells.
  • Antigen processing refers to the intracellular mechanisms by which antigens are degraded into smaller peptide fragments. This process occurs within antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells. The antigens can be derived from various sources, including intracellular pathogens, extracellular pathogens that have been engulfed by phagocytosis, or endocytosed antigens.
  • During antigen processing, the antigens are broken down into peptide fragments through enzymatic degradation. This typically occurs within cellular compartments such as lysosomes or endosomes, where proteolytic enzymes break down the proteins. The resulting peptide fragments are usually 8-20 amino acids in length.
  • Following antigen processing, the peptide fragments associate with specialized proteins called major histocompatibility complex (MHC) molecules. MHC molecules are of two types: MHC class I and MHC class II. MHC class I molecules present peptides derived from intracellular antigens, while MHC class II molecules present peptides from extracellular antigens.
  • In MHC class I antigen presentation, the processed peptide fragments are loaded onto MHC class I molecules within the endoplasmic reticulum (ER) of the antigen-presenting cell . The MHC class I-peptide complex is then transported to the cell surface, where it can be recognized by CD8+ T cells. This interaction triggers an immune response against infected or abnormal cells.
  • In MHC class II antigen presentation, the processed peptide fragments associate with MHC class II molecules within endosomes or lysosomes. MHC class II molecules are produced in the ER and associate with an invariant chain to prevent premature binding of self-peptides. In the endosomal compartments, the invariant chain is degraded, allowing the peptide fragments to bind to the MHC class II molecules. The MHC class II-peptide complex is then transported to the cell surface, where it can be recognized by CD4+ T cells, leading to immune activation.
  • The process of antigen processing and presentation is crucial for the immune system to distinguish between self and non-self antigens. It allows T cells to recognize and mount immune responses against foreign pathogens, infected cells, or abnormal cells. Understanding antigen processing and presentation is vital for studying immune responses, vaccine development, and the treatment of various diseases.

Major histocompatibility complex

  • MHC-encoded proteins were first identified in the 1930s during studies of tissue rejection in transplantation experiments.
  • Therefore, these proteins were given the name histocompatibility (histo meaning “tissue” and compatibility meaning “getting along”).
  • The genes influencing the histocompatibility of tissue transplantation have been mapped to a wide genomic area with several loci, hence the word “complex.”
  • Moreover, it was discovered that the proteins generated by these genes had profound effects on histocompatibility. To differentiate these proteins from others (encoded elsewhere in the genome) that had very minimal impacts on histocompatibility, these molecules were dubbed “major” histocompatibility molecules.
  • Thus, the genes encoding these proteins were designated as MHC genes ( major histocompatibility complex genes). Soon later, it was shown that MHC-controlled rejection of transplanted tissue was caused by the recipient’s immunological reaction to the donor cells.
  • Although this observation suggested that MHC gene products were directly engaged in immune responses , it took immunologists several more decades to establish the physiological role of MHC-encoded proteins in presenting antigenic peptides to T cells.
  • MHC class I and MHC class II molecules are the MHC-encoded proteins involved in the majority of antigen recognition by T lymphocytes. TCRs of CD8+ T cells identify MHC class I-bound peptides, whereas TCRs of CD4+ T cells recognise MHC class II-bound peptides.
  • Additionally, the CD8 coreceptor of CD8+ T cells attaches to MHC class I, whereas the CD4 coreceptor of CD4+ T cells binds to MHC class II. The MHC class I protein is a heterodimer composed of a long transmembrane α chain that is non-covalently connected to β2-microglobulin (β2m).
  • The MHC class I α chain, but not β2m, is encoded within the MHC. Class II MHC protein consists of a α chain and a somewhat smaller β chain, both of which are transmembrane proteins encoded by MHC genes.
  • With the exception of the peptide-binding groove, the tertiary structures of MHC class I and class II molecules are extremely similar despite this change in composition.
  • While virtually all nucleated cells express MHC class I, only a few cell types that serve as APCs (such as DCs, macrophages, and B cells) express MHC class II.
  • Consequently, virtually any cell can serve as a target cell and provide antigen to CTLs produced from CD8+ Tc cells, whereas only APCs can activate CD4+ Th cells.

Major histocompatibility complex I (MHC Class I)

  • The Major Histocompatibility Complex I (MHC Class I) is an important component of the immune system. It is the first class of the MHC molecule and is responsible for encoding glycoproteins that are expressed on the surface of nearly all nucleated cells in the body, with the exception of cells in the retina and brain.
  • The primary function of MHC Class I molecules is to present antigen-processed peptides to T-cytotoxic cells, also known as CD8+ T cells. This presentation occurs through the cytosolic pathway, where intracellular proteins are broken down into smaller peptide fragments. These peptides are then loaded onto MHC Class I molecules and transported to the cell surface for recognition by CD8+ T cells. This interaction is crucial for the immune system to identify infected or abnormal cells and mount an appropriate immune response, such as destroying the infected cells.
  • In humans, the MHC Class I protein is encoded by three genes known as HLA-A, HLA-B, and HLA-C. These genes are highly polymorphic, meaning they have many different alleles within the population. This diversity allows the immune system to recognize a wide range of pathogens and adapt to new infectious agents.
  • MHC Class I molecules are composed of two chains. The first chain is a transmembrane glycoprotein with a molecular weight of approximately 45,000. The second chain is a non-MHC-encoded polypeptide called β2-microglobulin, with a molecular weight of around 12,000. The association between these two chains is noncovalent, meaning they are not linked by a chemical bond. Together, they form the functional MHC Class I molecule.
  • The expression of MHC Class I molecules is widespread throughout the body, with the exception of cells in the retina and brain. This broad distribution ensures that infected or abnormal cells can be recognized and targeted by the immune system. By presenting antigenic peptides on their surface, MHC Class I molecules play a vital role in immune surveillance and defense against pathogens.
  • Understanding the structure and function of MHC Class I molecules is crucial in various areas of immunology and medicine, including transplantation, autoimmune diseases, and vaccine development. By studying these molecules, researchers can gain insights into the immune response and develop strategies to modulate or enhance immune reactions for therapeutic purposes.

MHC class I molecules

Structure of MHC Class I

  • The structure of MHC Class I molecules is composed of two polypeptide chains, which differ significantly in size. In both humans and mice, the larger chain, known as the α chain, has a molecular weight of approximately 44 kDa in humans and 47 kDa in mice. This α chain is encoded by an MHC Class I gene. The smaller chain, called β-2 microglobulin, has a molecular weight of around 12 kDa in both species and is encoded by a nonpolymorphic gene located outside of the MHC complex.
  • The structure of the α chain is highly conserved among different loci. There are no known structural differences between the α chains encoded by the HLA-A, HLA-B, and HLA-C loci in humans, or between the α chains encoded by the H-2K, H-2D, and H-2L loci in mice.
  • The α chain of MHC Class I molecules can be divided into several regions or domains. These include the peptide-binding domain , the immunoglobulin-like domain, the transmembrane domain, and the cytoplasmic domain. The peptide-binding domain, located at the N-terminal end of the α chain, is the region where allelic differences in the amino acid sequence can be found. This domain contains the site where antigenic peptides bind. The presence of allelic differences in the peptide-binding domain affects the ability of MHC Class I molecules to accommodate peptides, which, in turn, influences the magnitude of the T-cell response.
  • X-ray crystallography studies have revealed that the peptide-binding site of MHC Class I molecules forms a cleft with a “floor” and two “walls” created by spiral-shaped portions of the α chain known as alpha 1 and alpha 2. The closed “floor” of the cleft restricts the accommodation of relatively small peptides consisting of 9 to 11 amino acid residues.
  • The immunoglobulin-like domain of the α chain is structurally conserved and resembles a domain found in the constant region of antibodies (C-region). This domain contains the binding site for the T-cell accessory molecule CD8.
  • The transmembrane and cytoplasmic domains of the α chain ensure that it spans the cell membrane and is properly expressed by the cell. The β-2 microglobulin chain is essential for the proper expression of the α chain. Mutant lymphoid cell lines, such as Daudi, fail to express MHC Class I molecules due to defects in the β-2 microglobulin gene.

Class I major histocompatibility complex

Major histocompatibility complex II (MHC Class II)

  • Major Histocompatibility Complex II (MHC Class II) molecules are essential components of the immune system involved in antigen presentation. They are encoded by the class II MHC genes, primarily expressed on antigen-presenting cells such as macrophages, dendritic cells, and B cells. These MHC Class II molecules play a crucial role in presenting processed antigenic peptides to CD4+ T helper (TH) cells.
  • The genes responsible for encoding class II MHC proteins are located within the HLA-D region. Within this region, there are three families of molecules known as DP, DQ, and DR-encoded molecules. These different families contribute to the diversity of MHC Class II molecules, enabling the immune system to recognize and respond to a wide range of antigens.
  • The MHC Class II molecules play a vital role in regulating immune responsiveness. The allelic forms of the HLA-D genes confer variations in the ability to mount an immune response against specific antigens. This diversity in MHC Class II alleles is essential for the immune system’s capacity to recognize and respond to a diverse array of pathogens.
  • The proteins encoded by the HLA-D locus consist of two noncovalently associated transmembrane glycoproteins. The molecular weight of these chains is approximately 33,000 and 29,000, respectively. The expression of MHC Class II molecules is not ubiquitous but rather has a restricted tissue distribution. They are primarily found on macrophages, dendritic cells, B cells, and other antigen-presenting cells. However, under the influence of interferon-gamma (IFN-γ), MHC Class II molecules can also be expressed on other cell types such as endothelial cells and epithelial cells. This induction of MHC Class II expression expands the antigen-presenting capability to a broader range of cells, facilitating immune responses in various tissues.
  • The interaction between MHC Class II molecules and CD4+ T helper cells is crucial for the activation of the adaptive immune response. The antigenic peptides presented by MHC Class II molecules to TH cells help in coordinating immune responses and initiating appropriate effector mechanisms.

MHC class II molecules

Structure of MHC Class II

  • The structure of Major Histocompatibility Complex II (MHC Class II) molecules consists of two polypeptide chains, known as the alpha (α) chain and the beta (β) chain. Both humans and mice have similar-sized α and β chains, with molecular weights ranging from 32 to 34 kDa for the α chain and 29 to 32 kDa for the β chain. Each chain is controlled by a separate gene, resulting in polymorphic variations in both the α and β chains.
  • Some MHC Class II loci, particularly the β genes, can be tandemly duplicated. This means that instead of having one gene per homologous chromosome, a cell can possess two or three copies of the β gene. Consequently, a single cell can express multiple allelic products of each MHC Class II locus. This tandem duplication phenomenon enables a cell to simultaneously express up to 20 different MHC Class II gene products. For instance, a cell can express allelic products identified as HLA-DRα1– HLA-DRβ1, HLA-DRα2 – HLA-DRβ2, HLA-DRα1 – HLA-DRβ2, HLA-DRα2 – HLA-DRβ1, and so on.
  • The structure of the α and β chains of MHC Class II molecules shares similarities with the α chain of MHC Class I molecules. Both chains can be divided into the peptide-binding domain, the immunoglobulin-like domain, the transmembrane domain, and the cytoplasmic domain.
  • One notable difference is that the peptide-binding cleft in Class II molecules is formed by both the alpha and beta chains. Although the alpha and beta chains are positioned closely together, they are not physically bound to each other. Consequently, the peptide-accommodating cleft in Class II MHC molecules has an “open” or “hole-like” floor. This structural feature allows MHC Class II molecules to accommodate larger peptides compared to the peptides that fit into MHC Class I molecules.
  • The immunoglobulin-like domain of MHC Class II molecules contains a binding site for the T-cell accessory molecule CD4. However, this site cannot bind the CD8 molecule, which is associated with MHC Class I molecules.

Major Histocompatibility Class III (MHC Class III)

  • Major Histocompatibility Complex Class III (MHC Class III) genes are responsible for encoding a diverse range of secreted proteins that play critical roles in immune functions. These proteins include components of the complement system, which is a group of proteins involved in the body’s defense against pathogens.
  • The complement system consists of a cascade of proteins that work together to eliminate pathogens, enhance phagocytosis, and promote inflammation. Some of the proteins encoded by MHC Class III genes, such as C2, C4, and factor B, are part of the complement system. These proteins participate in the activation and regulation of the complement cascade, helping to clear pathogens and promote immune responses.
  • In addition to complement components, MHC Class III genes also encode various cytokines and other molecules involved in inflammation. Cytokines are signaling proteins that mediate immune responses and regulate the communication between immune cells. Examples of cytokines encoded by MHC Class III genes include tumor necrosis factor alpha (TNF-α) and lymphotoxin alpha (LT-α). These cytokines play crucial roles in initiating and modulating inflammatory responses, which are essential for combating infections and promoting tissue repair.
  • MHC Class III genes contribute significantly to the immune system’s ability to mount effective immune responses against pathogens. The secreted proteins encoded by these genes participate in key immune processes, including complement activation, inflammation, and cytokine-mediated signaling. Understanding the functions and regulation of MHC Class III genes and their protein products is crucial for unraveling the complexities of the immune system and developing therapies targeting immune-related disorders.

Antigen Processing and Presentation

  • Antigen processing and presentation are essential steps in the immune response that enable T lymphocytes to recognize and respond to protein antigens. This process involves the degradation of antigens into peptides, their association with Major Histocompatibility Complex (MHC) molecules, and their subsequent display on the cell membrane.
  • Antigen processing begins with the internalization of the protein antigens by antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells. Within these cells, the antigens are broken down into smaller peptide fragments through enzymatic degradation, a process known as antigen processing.
  • Once the antigens are processed into peptides, they associate with MHC molecules within the cell’s cytoplasm, forming a peptide-MHC complex. In the case of MHC Class I molecules, the peptides derived from endogenous antigens are processed within the cytoplasm of the cell. These endogenous antigens can include tumor proteins, viral proteins, bacterial proteins, or cellular proteins. The Class I MHC molecules bind these peptides and present them on the cell surface. This process is known as the cytosolic pathway.
  • On the other hand, MHC Class II molecules bind peptides derived from exogenous antigens that are taken up by the cell through phagocytosis or endocytosis. These exogenous antigens can include extracellular bacteria, viruses, or other foreign particles. The antigens are processed within the endocytic pathway, where they are degraded into peptides. The resulting peptides associate with Class II MHC molecules and are transported to the cell membrane, where they are displayed for recognition by CD4+ T helper cells. This process is called the endocytic pathway.
  • By presenting antigen-derived peptides, both MHC Class I and Class II molecules play crucial roles in activating T lymphocytes. The interaction between the T cell receptor on T lymphocytes and the peptide-MHC complex on antigen-presenting cells is central to initiating an immune response against specific antigens. This recognition triggers a cascade of immune reactions, leading to the activation and proliferation of T lymphocytes and the coordination of various immune effector mechanisms.
  • Antigen processing and presentation ensure that T lymphocytes can recognize a diverse array of antigens, whether they originate from intracellular sources (MHC Class I pathway) or extracellular sources (MHC Class II pathway). This process is fundamental for the adaptive immune response and plays a critical role in immune surveillance, defense against infections, and the elimination of abnormal or infected cells.

1. Cytosolic pathway – Endogenous antigen

  • The cytosolic pathway is responsible for processing and presenting endogenous antigens using Class I MHC molecules. This pathway involves several steps that culminate in the display of antigenic peptides on the cell surface for recognition by cytotoxic T lymphocytes.
  • The process begins with the degradation of intracellular antigen proteins into short peptides. This degradation occurs in the cytosol and is mediated by a proteolytic system that involves the attachment of a small protein called ubiquitin to the target proteins. The ubiquitin-protein conjugate is then recognized and degraded by a large protease complex known as the proteasome. The proteasome consists of four rings of protein subunits and has a central channel where the degradation of the ubiquitin-protein complex takes place.
  • Following degradation, the resulting peptides need to be transported from the cytosol to the rough endoplasmic reticulum (RER) where Class I MHC molecules are located. This transportation is facilitated by a transporter protein called TAP (transporter associated with antigen processing). TAP is a membrane-spanning heterodimer composed of two proteins, TAP1 and TAP2, and it mediates the ATP-dependent transport of peptides from the cytosol into the RER. TAP proteins preferentially transport peptides of 8-10 amino acids in length, which is optimal for binding to Class I MHC molecules. Peptides with hydrophobic or basic carboxyl-terminal amino acids, which are preferred anchor residues for Class I MHC molecules, are favored by TAP for transport.
  • Once the peptides reach the RER, they encounter chaperone molecules that assist in their folding and assembly with Class I MHC molecules. The alpha and beta-2-microglobulin components of Class I MHC molecules are synthesized on the rough endoplasmic reticulum. Calnexin, a resident membrane protein of the ER, associates with the Class I alpha chain and promotes its folding. When the beta-2-microglobulin binds to the alpha chain, calnexin is released, and the Class I molecule associates with the chaperone calreticulin and tapasin.
  • Tapasin, a TAP-associated protein, brings the TAP transporter into proximity with the Class I molecule, allowing it to acquire an antigenic peptide. The physical association between the alpha chain-beta-2-microglobulin heterodimer and the TAP protein promotes peptide capture by the Class I molecule before the peptides are exposed to the RER. Peptides that fail to bind to Class I molecules are rapidly degraded.
  • The formation of disulfide bonds during the maturation of Class I chains is facilitated by an additional chaperone protein called ERp57, which associates with calnexin and calreticulin complexes. Although the precise role of ERp57 in the Class I peptide assembly and loading process is not fully understood, it is believed to contribute to the maturation of Class I chains.
  • Once the Class I molecule has acquired an antigenic peptide, it gains increased stability and dissociates from calreticulin and tapasin. It then exits the RER and proceeds to the cell surface via the Golgi apparatus. The loaded Class I MHC molecules are displayed on the cell membrane, allowing them to present the antigenic peptides to cytotoxic T lymphocytes for immune recognition and response.
  • In summary, the cytosolic pathway is responsible for processing and presenting endogenous antigens using Class I MHC molecules. This pathway involves the degradation of antigen proteins, facilitated by the proteasome, followed by the transport of peptides into the RER via TAP proteins. The peptides are then assembled with Class I MHC molecules with the assistance of chaperone molecules, leading to the display of peptide-MHC complexes on the cell surface for immune surveillance and response.

2. Endocytic Pathway – Exogenous antigen

  • The endocytic pathway is responsible for processing and presenting exogenous antigens using Class II MHC molecules. This pathway involves the internalization of antigens by antigen-presenting cells (APCs) through processes such as phagocytosis, pinocytosis, or receptor-mediated endocytosis.
  • APCs like macrophages can internalize antigens by both phagocytosis and endocytosis, while other APCs, such as B cells, primarily internalize antigens through receptor-mediated endocytosis using antigen-specific membrane antibody receptors. Once the exogenous antigen is internalized, it undergoes degradation into peptides within the compartments of the endocytic processing pathway.
  • The endocytic pathway consists of several acidic compartments, including the early endosome (pH 6.0-6.5), late endosome or endolysosomes (pH 5.0-6.0), and lysosomes (pH 4.5-5.0). As the antigen moves through these compartments, the pH progressively decreases, creating an environment conducive to the activity of hydrolytic enzymes present in the lysosomes. These enzymes, including proteases, nucleases, glycosidases, lipases, phospholipases, and phosphatases, break down the antigen into smaller oligopeptides comprising 13-18 amino acid residues that can bind to Class II MHC molecules.
  • Transport vesicles facilitate the movement of the peptides from one compartment to the next within the endocytic pathway. Once the peptides reach the final compartments, they can be recycled back to the cell periphery by fusing with the plasma membrane , allowing for the recycling of surface receptors.
  • To prevent the binding of MHC II molecules to the same set of antigenic peptides as MHC I molecules, mechanisms exist to regulate peptide binding. When MHC II molecules are synthesized within the rough endoplasmic reticulum (RER), they associate with a protein called the invariant chain (Ii, CD74). The invariant chain interacts with the peptide-binding cleft of the MHC II molecules, preventing endogenously derived peptides from binding while the MHC II is in the RER. The invariant chain is also involved in the folding of MHC II molecules, their exit from the RER, and their routing to the endocytic processing pathway via the trans-Golgi network and endocytic vesicles.
  • As the MHC II-invariant chain complexes progress through the endocytic pathway, the invariant chain is gradually degraded, leaving a short fragment known as the CLIP (Class II-associated invariant chain peptide) bound to the MHC II molecule within the endosomal compartment. CLIP occupies the peptide-binding groove of the MHC II molecule, preventing premature binding of antigenic peptides.
  • The exchange of CLIP for antigenic peptides is facilitated by a molecule called HLA-DM. HLA-DM catalyzes the exchange reaction, promoting the binding of antigenic peptides to the MHC II molecule. HLA-DO, a molecule similar in structure to HLA-DM, modulates the function of HLA-DM, potentially affecting the efficiency of the exchange reaction.
  • In summary, the endocytic pathway is involved in the processing and presentation of exogenous antigens using Class II MHC molecules. Antigens are internalized by APCs through various endocytic mechanisms, undergo degradation within acidic compartments, and eventually bind to MHC II molecules after the removal of the invariant chain fragment CLIP. The exchange of CLIP for antigenic peptides is facilitated by HLA-DM, while HLA-DO helps regulate the function of HLA-DM in this process.

Presentation of Non-peptide antigens

  • Non-peptide antigens can also elicit immune responses and are recognized by a specific subset of T-cell receptors known as δγ-TCR. These T-cell receptors are dimers of αβ and δγ chains and are derived from glycolipids found in bacterial pathogens like Mycobacterium tuberculosis.
  • The presentation of non-peptide antigens is mediated by a group of molecules called CD1, which are nonclassical class I molecules. The CD1 family of molecules associates with β2-microglobulin and shares structural similarities with MHC class I molecules. In humans, there are five CD1 genes (CD1A, CD1B, CD1C, CD1D, and CD1E), although CD1E has not been identified yet. These genes are located on chromosomes and not within the MHC I region.
  • The CD1 molecules are divided into two groups based on sequence homology. Group 1 includes CD1A, CD1B, CD1C, and CD1E, while CD1D belongs to group 2. Different species have varying numbers of CD1 genes. For example, rodents only have group 2 CD1 genes, whereas humans and rabbits have five genes, encompassing both group 1 and group 2 CD1 types.
  • The sequence identity between CD1 molecules and classical class I MHC molecules is relatively lower compared to the sequence identity among class I MHC molecules themselves. CD1D1, for instance, exhibits a deeper and more voluminous antigen-binding groove than class I MHC molecules.
  • These unique structural features of CD1 molecules allow them to bind and present non-peptide antigens, such as glycolipids derived from bacterial pathogens. The interaction between CD1 molecules and δγ-TCR on T cells enables the recognition and immune response against these non-peptide antigens.
  • In summary, non-peptide antigens derived from bacterial pathogens can be recognized by δγ-TCR on T cells. These antigens are presented by CD1 molecules, a family of nonclassical class I molecules. CD1 molecules have distinct structural characteristics and exhibit sequence variations compared to classical class I MHC molecules. Their ability to bind and present non-peptide antigens contributes to the immune response against infections caused by pathogens like Mycobacterium tuberculosis.

Clinical Significance of Antigen processing and presentation

  • The process of antigen processing and presentation plays a crucial role in various clinical conditions, including autoimmune diseases. In some cases, antigen-presenting cells (APCs) can present self-antigens, leading to the initiation of an immune reaction against our own tissues. This immune dysregulation can result in autoimmune disorders such as Graves’ disease and rheumatoid arthritis.
  • Graves’ disease, for instance, involves the presentation of self-antigens related to the thyroid gland. In this condition, the self-antigen Thyroid-stimulating hormone receptor (TSHR) is presented to T-cells by APCs. This interaction activates B-cells, leading to the production of autoantibodies against TSHRs present in the thyroid. As a consequence, the TSHRs become activated, causing hyperthyroidism and resulting in the enlargement of the thyroid gland, known as goiter.
  • This autoimmune process in Graves’ disease highlights the clinical significance of antigen processing and presentation. It demonstrates how the incorrect presentation of self-antigens can trigger an immune response against our own tissues, leading to the development of autoimmune disorders. Similar mechanisms can occur in other autoimmune diseases, where self-antigens are presented to T-cells, resulting in the production of autoantibodies and subsequent tissue damage.
  • Understanding the underlying mechanisms of antigen processing and presentation is crucial for unraveling the pathogenesis of autoimmune diseases. It can provide insights into the development of targeted therapies aimed at modulating the immune response and restoring immune tolerance to self-antigens. By regulating antigen presentation, it may be possible to prevent or attenuate the autoimmune response, providing potential therapeutic avenues for managing these complex disorders.
  • In summary, the clinical significance of antigen processing and presentation lies in its association with autoimmune diseases. Dysregulated presentation of self-antigens can lead to the activation of the immune system against our own tissues, contributing to conditions such as Graves’ disease. Further research into the mechanisms involved in antigen processing and presentation holds promise for the development of novel treatments for autoimmune disorders.

MHC Class I Antigen-Processing Pathway

  • In general, antigens presented by MHC class I and class II molecules originate from distinct cellular compartments.
  • The antigen processing route for MHC class I antigens begins in the cytosol with the breakdown of an endogenous self-protein. After microbial infection, intracellular proteins produced from microbes enter the MHC class I processing pathway.
  • Cross-presentation is a mechanism through which extracellular host or microbe proteins that have been absorbed into membrane-bound compartments via endocytosis or phagocytosis can enter the MHC class I processing pathway.
  • Proteasomes breakdown misfolded or unnecessary proteins through proteolysis in the cytoplasm, thereby regulating the protein composition of the cell. These multicomponent proteases have a barrel shape and are composed of four rings containing seven subunits apiece.
  • Proteasomes degrade proteins by a variety of methods. Misfolded proteins and faulty ribosomal products, which both fail to assume their native conformation states, may expose peptide sequences that are identified by proteasomes, resulting in their fast destruction.
  • Alternatively, numerous proteins destined for fast proteasomal breakdown are conjugated to ubiquitin by enzymes that identify the phosphorylation of particular amino acids.
  • Proteasomal breakdown of microbial antigens is essential for the presentation of microbial peptides by MHC class I proteins during microbial infection.
  • Some proteasomal subunits are replaced by others that improve the formation of antigenic peptides, and other components are introduced to the ends of the barrel to alter the effectiveness and specificity of protein degradation in activated cells or after exposure to IFN-γ.
  • It is unknown if pathogen-derived polypeptides and proteins are degraded selectively and targeted for presentation by MHC class I molecules during an infection.
  • Bacterial proteins that enter the cytosol are rapidly degraded due to the presence of unique amino-terminal amino acids or internal amino-acid sequences that promote fast breakdown.
  • In the majority of cases, pathogen-derived antigens are probably degraded nonselectively alongside indigenous proteins, and pathogen-derived peptides compete with more abundant endogenous peptides for a binding groove in MHC class I.
  • Proteasomes create peptides between 9 and 12 amino acids in length due to the length of the proteasome channel. Transporter Associated with Antigen Processing binds peptides synthesised by proteasomes (TAP).
  • This ATP-dependent, heterodimeric transporter efficiently transports peptides from the cytosol to the lumen of the endoplasmic reticulum.
  • Peptides less than 6 amino acids or longer than 14 amino acids are poorly transported by TAP.
  • TAP is the primary peptide transporter involved in the formation of peptide/MHC class I complexes; animals with genetic deletions of TAP have significantly reduced levels of surface MHC class I and significantly reduced numbers of CD8+ T lymphocytes.
  • Rarely identified in people, TAP deficiency is associated with a substantial reduction in circulating CD8+ T lymphocytes and mild immunodeficiency.
  • TAP1 and TAP2 molecules carry peptides from the cytosol to the endoplasmic reticulum lumen.
  • The development of the peptide loading complex involves the association of newly synthesised MHC class I molecules with TAP in the endoplasmic reticulum and the recruitment of many additional endoplasmic reticulum resident proteins and chaperones (PLC).
  • The PLC consists of the MHC class I/β2-microglobulin complexes coupled to tapasin, which serves as a molecular adapter for TAP, as well as calreticulin and thiol reductase ERp57.
  • The primary function of β2-microglobulin and the PLC is to maintain the shape of the MHC class I peptide-binding groove that favours the binding of high-affinity peptides. Due to the fact that TAP delivers numerous peptides into the endoplasmic reticulum lumen that are too long to fit into the MHC class I peptide–binding groove, the endoplasmic reticulum resident proteases ERAP1 and ERAP2 trim peptides prior to their final incorporation into the MHC class I peptide–binding groove.
  • If the affinity between peptide and MHC class I is high enough, the PLC releases the MHC class I/β2-microglobulin/peptide complex, allowing it to reach the cell surface via the Golgi complex. If the affinity between peptide and MHC class I is low, the MHC class I heavy chain undergoes re-glycosylation of an N-linked glycan, which redirects MHC class I molecules into the PLC for peptide exchange and blocks their release into the secretory pathway.
  • Inflammation controls the antigen processing pathway of MHC class I. IFN-γ in particular is a cytokine with numerous effects on the MHC class I pathway.
  • IFN-γ increases the transcription of numerous components of the MHC class I pathway, including MHC class I molecules, TAP, tapasin, and a number of proteasome components. Three proteasome subunits, LMP-2, LMP-7, and MECL, are specifically induced and replace three subunits of the core proteasome complex.
  • IFN-γ generates other accessory proteins that affect proteasome efficiency and specificity, with PA28, a six-subunit activator that forms rings that can cap the ends of the proteasome, playing a key role.
  • PA28 can enhance the presentation of MHC class I–restricted, virus-derived epitopes to CD8+ T lymphocytes.
  • In the presence of an infection, the MHC class I antigen processing pathway is amplified, allowing for greater presentation of pathogen-derived peptides to CD8+ T cells.

MHC Class I Antigen-Processing Pathway

Viral Intervention with the MHC Class I Antigen-Processing Pathway

  • CD8+ T cells and the MHC class I antigen processing pathway are primarily responsible for viral infection defence. Fascinatingly, viral infections have gone to great lengths to subvert the MHC class I antigen-processing pathway, highlighting the significance of this antiviral defence mechanism.
  • It was discovered early on that herpesvirus-infected cells downregulate MHC class I expression. Exploration of the mechanism underlying this discovery found numerous viral proteins that inhibit various MHC class I antigen processing pathway steps.
  • Herpes simplex virus encodes ICP47, which disrupts human TAP by blocking the peptide transport channel from the cytosolic side.
  • The human cytomegalovirus-encoded protein US6 hinders TAP transport by inhibiting the peptide transporter from the endoplasmic reticulum luminal side using a similar method but a completely different protein.
  • Additionally, human cytomegalovirus employs a number of additional ways to prevent MHC class I molecules from reaching the cell surface. US3 binds MHC class I molecules in the endoplasmic reticulum, preventing their transport to the cell surface.
  • Adenoviruses, which encode the type I membrane protein E3-19K, adopt a similar method. By expressing an endoplasmic reticulum retention motif on its cytoplasmic tail, this protein binds MHC class I molecules in the endoplasmic reticulum lumen and blocks their egress from the endoplasmic reticulum.
  • The displacement of MHC class I molecules residing in the endoplasmic reticulum into the cytoplasm, where they are promptly ubiquitinated and destroyed by proteasomes, is an additional method for downregulating surface MHC class I retention. Two human cytomegalovirus-encoded proteins, US2 and US11, are responsible for mediating this process.
  • Remarkably, transport of misfolded or otherwise dysfunctional proteins from the endoplasmic reticulum lumen to the cytosol via the Sec61 translocon is a normal mechanism.
  • US2 and US11 appear to expedite this process for MHC class I molecules alone. The binding of US2 to MHC class I molecules has been studied by x-ray crystallography .
  • Using a distinct mechanism, the Kaposi sarcoma herpesvirus also inhibits surface MHC class I expression. K3 and K5 expressed by the Kaposi sarcoma herpesvirus are ubiquitin ligases that specifically conjugate ubiquitin to the cytoplasmic tails of MHC class I and B7.2 co-stimulatory components.
  • Surface MHC class I molecules are rapidly absorbed and destined for lysosomal destruction upon ubiquitination. Additionally, HIV has evolved methods to inhibit surface expression of MHC class I molecules.
  • By connecting with the clathrin adaptor complex, the retrovirally generated Nef protein specifically downregulates the production of HLA-A and HLA-B molecules.
  • Importantly, the downregulation of MHC class I renders afflicted cells vulnerable to NK cell-mediated lysis. On contact with MHC class I molecules, NK cells express receptors that suppress NK cell activation.
  • To prevent NK cell–mediated lysis of virally infected cells, human CMV generates an MHC class I–like protein, UL18, which works as a decoy for the NK cell inhibitory receptor LIR-1, providing the viral pathogen with an additional layer of camouflage.

MHC Class I Cross-Priming

  • The antigen processing route for MHC class I has two primary functions. First, it delivers antigens to CD8+ T lymphocytes that are not yet activated, proliferating, or differentiating in a manner that promotes their activation, proliferation, and differentiation.
  • Second, it signals cellular infection to activated CD8+ T cells by presenting antigens. DCs mediate the first function largely, if not solely.
  • Any infected cell that expresses MHC class I can execute the second function. Different antigen processing criteria apply in these two instances. As discussed in the preceding sections, the normal MHC class I antigen processing pathway applies to the second function.
  • Pathogen-derived antigens are degraded and displayed on the cell surface in the presence of MHC class I molecules when cells are directly infected.
  • The presentation of MHC class I antigens by DCs is more complicated and is not limited to indigenous cytosolic proteins.
  • Due to the fact that CD8+ T-cells are rarely infected directly, the major route for CD8+ T-cell priming involves uptake of debris from infected cells by DCs and re-presentation of pathogen-derived peptides by an antigen-processing pathway involving endocytosis and TAP-mediated transport of antigen into the endoplasmic reticulum.
  • The CD8+ fraction of DCs is especially efficient at taking up and delivering exogenous antigens to the MHC class I antigen processing pathway.
  • Antigen-containing phagosomes in DCs fuse with endoplasmic reticulum membranes, which recruits retrotranslocation machinery that shuttles misfolded proteins or antigens from the phagosome lumen into the cytosol, where they are degraded by proteasomes and enter the conventional MHC class I processing pathway.
  • This convoluted route for CD8+ T-cell priming guarantees that CD8+ T-cell priming happens in a regulated manner and is likely a critical barrier to prevent excessively powerful CD8+ T-cell responses to systemic viral infections.

MHC Class II Antigen-Processing Pathway

  • The antigen processing pathway of MHC class II provides peptides to CD4+ T cells. Although there are similarities to the MHC class I antigen processing system, there are significant differences.
  • Firstly, the majority of peptides presented by MHC class II molecules originate from extracellular proteins endocytosed by MHC class II– expressing cells.
  • During transport to the cell surface, MHC class II molecules also display peptides from membrane or secretory proteins that have been degraded in endosomal compartments.
  • Regarding antimicrobial responses, the MHC class II antigen-processing pathway has been associated mostly with the response to extracellular pathogens and vacuolar-dwelling pathogens, such as S. typhimurium and M. tuberculosis.
  • Due to the fact that CD4+ T-cell responses are also necessary for the complete priming, activation, and differentiation of CD8+ T-cell responses, it is difficult to directly attribute immunological vulnerability to CD4+ T-cell deficit.
  • The HIV epidemic has made the ramifications and complications of CD4+ T-cell depletion evident.
  • The initial stage in the processing of MHC class II antigens is the translocation and assembly of MHC class II α- and β-chains in the endoplasmic reticulum, a mechanism regulated by a chaperone, the invariant chain.
  • In the endoplasmic reticulum, MHC class II molecules do not bind antigenic peptides. The α- and β-chains fold by substituting the membrane-bound protein invariant chain for peptide.
  • As the complex exits the endoplasmic reticulum, traverses the Golgi complex, and travels to the endosomal compartments, a fragment of the invariant chain fills the MHC class II groove.
  • On acidification of the endosomal compartment, proteases such as cathepsin D and cathepsin B are activated and destroy all portions of the invariant chain excluding the section that is protected by the MHC class II groove.
  • During the degradation process, MHC class II molecules might interact with endocytosed antigens in the acidified endosome compartment known as MIIC.
  • The invariant chain segment is replaced by a proteolytically produced peptide in a complex, topologically demanding sequence of events.
  • Similar to MHC class I molecules, MHC class II molecules are selective with regard to peptide binding; however, because the groove is open and can accommodate peptides in different registers, the range of peptides that are bound is expanded and the binding rigour is loosened.
  • HLA-DM, an MHC-encoded, MHC-class II-like protein that dwells in MIICs, accelerates the binding mechanism of MHC class II peptides.
  • Recent crystallographic investigations demonstrate that HLA-DM stabilises empty MHC class II proteins in a conformation that favours the insertion of a high-affinity peptide. HLA-DM catalyses the extraction of the invariant chain peptide fragment from the MHC class II molecule.
  • In addition to proteases, GILT (gamma interferon–inducible lysosomal thioreductase) is involved in the denaturation of certain antigens prior to their breakdown and presentation by MHC class II molecules.
  • GILT has also been linked to the activation of the primary secreted virulence factor of the bacterial pathogen L. monocytogenes, listeriolysin-O, offering an exceptional example of microbial exploitation of antigen-processing pathways.
  • Upon peptide attachment in the MIIC, MHC class II molecules travel to the cell surface, where CD4+ T lymphocytes can detect the MHC class II/peptide complex. MHC class II molecules undergo re-internalization, and it is possible that these complexes recycle to endosomal compartments and acquire new peptides before returning to the cell surface.
  • Uncertainty surrounds the contribution of this pathway to the MHC class II antigen processing pathway during immunological responses to infection.

The major histocompatibility complex (MHC) class II antigen-processing pathway

What is CD1?

  • The CD1 family contains antigen-presenting molecules that are structurally similar to MHC class I molecules and are associated with β2-microglobulin.
  • Human chromosome 1’s CD1 locus has five different genes that code for the proteins CD1a through CD1e.
  • Consistent with their structural resemblance to MHC class I, CD1 molecules are often strongly expressed on antigen-presenting cells, present antigens for TCR recognition, and interact with T lymphocytes. CD1 molecules differ significantly from MHC molecules in the class of displayed antigens.
  • In contrast to the peptide antigens presented by the MHC, CD1 proteins present lipid and glycolipid antigens to T cells, a discovery that dramatically increased the number of antigens recognised by T lymphocytes.
  • The illustration depicts the structure of the human CD1b molecule displaying ganglioside GM2.
  • This section discusses the antigens given by CD1, the lymphocytes that identify these antigens, and the significance of this antigen-presenting system in the defence of the host against specific infectious illnesses.

CD1 Protein Structure

  • CD1 proteins are transmembrane proteins with a brief intracellular domain. The extracellular component of CD1 consists of three antigen-binding domains, while particular patterns in the intracellular region regulate CD1 trafficking to intracellular compartments (see later discussion).
  • The antigen-binding groove formed by the extracellular domains of CD1 molecules is structurally similar to the peptide-binding groove of the MHC.
  • Consistent with CD1’s function of lipid presentation, the antigen-binding groove has several hydrophobic pockets that can accept the aliphatic chains of lipid antigens.
  • The three-dimensional structure of mouse CD1266 and human CD1b265 reveals a complex network of hydrophobic channels capable of accommodating various lipids with differing aliphatic chain lengths.
  • In contrast to the five CD1 isoforms found in humans, mice lack CD1a, CD1b, and CD1c and possess two copies of the CD1d gene.
  • This significant difference between mouse and human CD1 hampers the experimental analysis of CD1 function since genetically modified mice cannot be used to examine the function of CD1a, CD1b, and CD1c.

Structure of CD1b in complex with a lipidic antigen

Antigens Presented by CD1

  • T lymphocytes are presented with lipid and glycolipid antigens from various bacteria and fungi by CD1. CD1-presented antigens include diacylglycerols from S. pneumoniae, a fungal glycosphingolipid (i.e., asperamide B), and a marine sponge-derived synthetic glycolipid, -galactosyl ceramide.
  • These last three chemicals are delivered to NKT cells in a CD1-restricted way, and -galactosyl ceramide has been utilised extensively to explore the effect of CD1d-mediated NKT-cell activation on the host’s defence against infections and malignancies.
  • CD1 is essential for delivering mycobacterial lipids to T lymphocytes, particularly glycosylated and free mycolic acids and lipoarabinomannan, two key lipid and glycolipid components of M. tuberculosis cell envelope.
  • Further investigations of the structure of CD1-presented lipids indicated that T-cell recognition of CD1b-presented glycolipids was extraordinarily sensitive to the fine structure of the carbohydrate head group, but rather insensitive to structural changes in the lipid tail.
  • Together, these observations and the subsequent characterization of CD1c-presented mycobacterial isoprenoid glycolipids have led to a model of CD1 lipid antigen presentation in which the hydrophilic head group is exposed and available for TCR interactions while the hydrophobic lipid tails of the antigen are bound within the hydrophobic pockets of the CD1 protein.

Cell Biology of CD1 Antigen Processing and Loading

  • CD1 isoforms are abundant in diverse intracellular compartments, indicating that each isoform of CD1 has evolved to detect microbial antigens that are present in unique regions of the endosomal lysosomal network.
  • The figure provides a summary of CD1 trafficking pathways. Endocytosis results in the internalisation of all CD1 isoforms at the cell surface. C D1a is primarily found in early endosomes, CD1c in late endosomes, and CD1b/d in both late endosomes and lysosomes.
  • Specific amino acid residues in the short intracellular tails of CD1 isoforms bind to cytosolic adaptor molecules that mediate organelle trafficking, thereby targeting these isoforms to their respective compartments.
  • Although the specific physiological ramifications of this trafficking pattern for the immune response are still being explored, each CD1 isoform may survey a unique intracellular compartment for unique lipid structures from unique pathogens.

Intracellular trafficking of CD1 isoforms.

What is antigen processing and presentation?

Antigen processing and presentation is a crucial immune process in which cells capture, process, and display antigens to activate T-cells, leading to an immune response.

What are the main cells involved in antigen processing and presentation?

Antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells are primarily responsible for antigen processing and presentation.

How are antigens processed within cells?

Antigens can be processed within cells through two main pathways: the cytosolic pathway (for endogenous antigens) and the endocytic pathway (for exogenous antigens).

What are MHC molecules and their role in antigen presentation?

Major Histocompatibility Complex (MHC) molecules are cell surface proteins that bind and display antigens to T-cells. MHC class I presents endogenous antigens, while MHC class II presents exogenous antigens.

How do MHC class I molecules present antigens?

MHC class I molecules present peptides derived from endogenous antigens that are processed within the cytoplasm of the cell. These peptides are then displayed on the cell surface to activate CD8+ cytotoxic T-cells.

How do MHC class II molecules present antigens?

MHC class II molecules present peptides derived from exogenous antigens that are internalized through phagocytosis or endocytosis. These peptides are processed within endocytic compartments and displayed on the cell surface to activate CD4+ helper T-cells.

What is the role of T-cell receptors (TCRs) in antigen recognition?

T-cell receptors (TCRs) are proteins expressed on the surface of T-cells that recognize and bind to specific antigens displayed by MHC molecules. TCRs play a crucial role in initiating the immune response.

Can non-peptide antigens be presented by MHC molecules?

Yes, non-peptide antigens, such as glycolipids, can be recognized and presented by nonclassical MHC molecules called CD1 proteins.

How does antigen processing and presentation contribute to autoimmune diseases?

In autoimmune diseases, the presentation of self-antigens can lead to the activation of T-cells against our own tissues, resulting in autoimmune reactions and tissue damage.

What is the importance of studying antigen processing and presentation?

Studying antigen processing and presentation helps us understand the mechanisms behind immune responses, including the development of protective immunity and autoimmune disorders. It also provides insights for designing vaccines and developing immunotherapies for various diseases.

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  • Li XC, Raghavan M. Structure and function of major histocompatibility complex class I antigens. Curr Opin Organ Transplant. 2010 Aug;15(4):499-504. doi: 10.1097/MOT.0b013e32833bfb33. PMID: 20613521; PMCID: PMC3711407.
  • Natarajan, K & Li, Hongmin & Mariuzza, RA & Margulies, David. (1999). MHC class I molecules, structure and function. Reviews in immunogenetics. 1. 32-46. 
  • Wieczorek, M., Abualrous, E. T., Sticht, J., Álvaro-Benito, M., Stolzenberg, S., Noé, F., & Freund, C. (2017). Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Frontiers in Immunology, 8. doi:10.3389/fimmu.2017.00292 
  • Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The major histocompatibility complex and its functions. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27156/
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Antigen processing and presentation: Cytosolic and Endocytic pathway

August 3, 2020 Gaurab Karki Immunology 0

Antigen processing and presentation: Cytosolic and Endocytic pathway

Antigen processing and Antigen presentation

  • Antigen processing is a metabolic process that digests the proteins into peptides which can be displayed on the cell membrane together with a class-I or class-II MHC molecules and recognized by T-cells.
  • Antigen presentation is the process by which certain cell in the body especially antigen presenting cells (APCs) express processed antigen on their cell surface along with MHC molecules in the form recognizable to T cell.
  • If antigen is presented along with class-I MHC molecule, it is recognized by CD8 + Tc-cell and if presented along with class-II MHC molecule, it is recognized by CD4 + TH cells.

On the basis of types of antigen to be processed and presented, antigen processing and presenting pathway are of two types:

Cytosolic pathway of antigen processing and presentation

  • Cytosolic pathway processed and presented the endogenous antigens i.e. those generated within cell eg. Viral infected cells, tumor cells and intracellular pathogens ( M . tuberculosis, Histoplasma capsulatum).
  • The processed antigen is presented on the cell membrane with MHC-class I molecule which is recognized by CD8 + Tc-cell for degradation.

Steps involved in cytosolic pathways are:

  • Proteolytic degradation of Ag (protein) into peptides
  • Transportation of peptides from cytosol to RER
  • Assembly of peptides with class I MHC molecules

i. Proteolytic degradation of proteins into peptides:

  • Intracellular proteineous antigen are larger in size to be bound to MHC molecule.
  • So, it is degraded into short peptides of about 8-10 amino acids.
  • These proteins are degraded by cytosolic proteolytic system present in cell called proteasome.
  • The large (20S) proteasome is composed of 14 sub-units arranged in barrel-like structure of symmetrical rings.
  • Some, but not all the sub-units have protease activity.
  • Proteins enter the proteasome through narrow channel at each end.
  • Many proteins targeted for proteolysis have a small protein called ubiquitin attached to them.
  • Ubiquitin attached to them ubiquitin-protein complex consisting of 20S proteasome and 19S regulatory component added to it.
  • The resulting 26S proteasome cleaves peptide bonds which is ATP-dependent process.
  • Degradation of ubiquitin protein complex is thought to occur within the central hollow of the proteasome to release peptides.

ii. Transportation of peptides from cytosol to Rough Endoplasmic Reticulum (RER):

  • Peptides generated in cytosol by proteasome are transported by TAP (transporter associated with antigen processing) into RER (Rough endoplasmic reticulum) by a process which require hydrolysis of ATP.
  • TAP is membrane spanning heterodimer consisting of two proteins, TAP1 and TAP2.
  • TAP has affinity for peptides having 8-16 amino acids.
  • The optimal peptide length required by class-I MHC for binding is nine, which is achieved by trimming the peptides with the help of amino-peptidase present in RER. Eg. ERAP.
  • In addition to it, TAP favor peptides with hydrophobic or basic carboxyl terminal amino acids, that preferred anchor residues for class-I MHC molecules.
  • TAP deficiency can lead to a disease syndrome that has both immune-deficiency and auto-immunity aspects.

iii. Assembly of peptides with class-I MHC molecule:

  • Like other proteins, the α-chain and β 2 microglobulin components of the class-I MHC molecule are synthesized on polysome along the rough endoplasmic reticulum.
  • Assembly of these components into stable class-I MHC molecule that can exit the RRE require binding of peptides into peptide binding groove of class-I MHC molecules.
  • The assembly process involves several steps and needs help of molecular chaperone.
  • The first molecular chaperone involved in assembly of class-I MHC is calnexin.
  • It is a resident membrane protein of RER.
  • Calnexin associated with free class-I α-chain and promotes its folding.
  • When β 2 -microglobulin binds class-I α-chain, calnexin is released and class-I MHC associates with another chaperone calreticulin and tapasin (TAP-associated protein).
  • Tapasin brings TAP transporter carrying peptides to the proximity with class-I MHC molecule and allows to acquire the antigenic peptides.
  • An additional protein with enzymatic activity, ERp57, form disulfide bond to tapasin and non-covalently associates with calreticulin to stabilize the interaction and allows release of MHC-I-class after acquiring antigenic peptides.
  • As a consequence, the productive peptide binding with MHC of class-I releases from the complex of calreticulin, tapasin and ERp57, exit from RER and displays on the cell surface via golgi complex.

process of antigen presentation

Endocytic pathway of antigen processing and presentation:

  • The endocytic pathway processed and present the exogenous Ag. i.e. antigens generated outside the cells. E.g. Bacteria.
  • At first APC phagocytosed, endocytosed or both, the antigen.
  • Macrophage and dendritic cells internalize the antigen by both the process.
  • While other APCs are non-phagocytic or poorly phagocytic. E.g. B cell internalize the antigen by receptor mediated endocytosis.
  • Then antigen is processed and presented on the cell surface along with class-II MHC molecules which are recognized by CD4 + TH cell.

Steps involved in endocytic pathway:

  • Peptide generation from internalized molecules (Ag) in endocytic vesicles.
  • Transport of class-II MHC molecule to endocytic vesicles.
  • Assembly of peptides with Class-II MHC molecules.

i. Peptide generation from internalized molecules (Ag) in endocytic vesicles:

  • Once an antigen is internalized, it is degraded into peptides within compartments of endocytic processing pathway.
  • The endocytic pathway appears to involve three increasingly acidic compartments, early endosomes (pH 6-6.5), late endosomes or endo-lysosome (pH 5-6) and lysosomes (pH 4.5-5).
  • The internalized antigens move from early to late endosomes and finally to lysosomes, encountering hydrolytic enzymes and a lower pH in each compartment.
  • Within the compartment, antigen is degraded into oligopeptides of about 13-18 residues.
  • The mechanism by which internalized Ag moves from one endocytic compartment to next has not been clearly demonstrated.
  • It has been suggested that early endosome move from periphery to inward to become late endosome and finally lysosomes.
  • Alternatively, small transport vesicles may carry Ag from one compartment to next.

ii. Transport of class-II MHC molecule to endocytic vesicles:

  • When class-II MHC molecules are synthesized within RER, three pairs of class-II αβ- chains associated with a pre-assembled trimer of a protein called invariant chain (Li, CD74).
  • This trimeric protein prevents any endogenously antigen to bind to the cleft.
  • The invariant chain consists of sorting signals in its cytoplasmic tail.
  • It directs the transport of class-II MHC molecule to endocytic compartments from the trans-golgi network.

iii. Assembly of peptides with class-II MHC molecules:

  • Class-II MHC-invariant chain complexes are transported from RER through golgi complex and golgi-network and through endocytic compartment, moving from early endosome to late endosome and finally to lysosome.
  • The proteolytic activities increase in each compartment, so the invariant is slowly degraded.
  • However, a short fragment of invariant chain remained termed as CLIP (Class-II associated invariant chain).
  • CLIP physically occupies the peptide binding, cleft of class-II MHC molecule, presumably preventing any premature binding of antigenic peptides.
  • A non-classical class-II MHC molecule known as HLA-DM is required to catalyze the exchange of CLIP with antigenic peptides.
  • The reaction between HLA-DO, which binds to HLA-DM and lessens the efficiency of the exchange reactions.
  • Conditions of higher acidity in endocytic compartment weakens the association of DM/DO and increase the possibility of antigenic peptide binding despite of DO.
  • As with class-I MHC molecule, peptide binding is required to maintain the structure and stability of class-II MHC molecules.
  • Once a peptide has bound the peptide-class II MHC complex is transported to the plasma membrane where neutral pH enables the complex to assume the compact and stable form.

process of antigen presentation

  • Antigen processing and presentationCytosolic and Endocytic pathway

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Cancer immune escape: the role of antigen presentation machinery

  • Open access
  • Published: 09 April 2023
  • Volume 149 , pages 8131–8141, ( 2023 )

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  • Anoop Kallingal   ORCID: orcid.org/0000-0002-9613-3259 1 ,
  • Mateusz Olszewski   ORCID: orcid.org/0000-0002-1952-4985 1 ,
  • Natalia Maciejewska   ORCID: orcid.org/0000-0001-9942-285X 1 ,
  • Wioletta Brankiewicz   ORCID: orcid.org/0000-0002-8314-0775 1 , 2 &
  • Maciej Baginski 1  

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The mechanisms of antigen processing and presentation play a crucial role in the recognition and targeting of cancer cells by the immune system. Cancer cells can evade the immune system by downregulating or losing the expression of the proteins recognized by the immune cells as antigens, creating an immunosuppressive microenvironment, and altering their ability to process and present antigens. This review focuses on the mechanisms of cancer immune evasion with a specific emphasis on the role of antigen presentation machinery. The study of the immunopeptidome, or peptidomics, has provided insights into the mechanisms of cancer immune evasion and has potential applications in cancer diagnosis and treatment. Additionally, manipulating the epigenetic landscape of cancer cells plays a critical role in suppressing the immune response against cancer. Targeting these mechanisms through the use of HDACis, DNMTis, and combination therapies has the potential to improve the efficacy of cancer immunotherapy. However, further research is needed to fully understand the mechanisms of action and optimal use of these therapies in the clinical setting.

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Introduction

The role of antigen presentation in cancer immune cell escape is a complex and multifaceted topic that has been the subject of much research in recent years. Antigen presentation is the process by which cells in the immune system display foreign molecules, such as those from pathogens or cancer cells, on their surface for recognition by other immune cells (Zitvogel and Kroemer 2018 ). In the context of cancer, antigen presentation plays a crucial role in the ability of the immune system to identify and target cancer cells. However, cancer cells can evade the immune system by various mechanisms, including downregulating or losing the expression of the proteins recognized by the immune cells as antigens, a process known as an immune escape (Beatty and Gladney 2015 ). The process of antigen presentation begins with the cancer cells expressing proteins on their surface, which are then recognized by specialized immune cells called antigen-presenting cells (APCs) (Mpakali and Stratikos 2021 ). These APCs, such as dendritic cells, then internalize the cancer cell proteins and degrade them into smaller peptides. These peptides are then displayed on the surface of the APC, along with particular proteins called major histocompatibility complex (MHC) molecules (Blum et al. 2013 ). The MHC molecules act as a bridge between the cancer cell proteins and the immune cells responsible for recognizing and attacking cancer cells, called T cells. The T cells have T cell receptors (TCRs) that can recognize the cancer cell proteins displayed on the MHC molecules (Alberts et al. 2002 ). When a T cell recognizes a cancer cell protein displayed on an APC, it becomes activated and begins to divide and differentiate into specialized cells that can attack and destroy the cancer cells (Messerschmidt et al. 2016 ). Cancer cells can evade the immune system by downregulating or losing the expression of the proteins recognized by the immune cells as antigens (Beatty and Gladney 2015 ). This can happen by mutations in the cancer cells that affect the expression of these proteins or by the cancer cells creating an immunosuppressive microenvironment that prevents the immune cells from recognizing and attacking the cancer cells (Brody 2016 ). Some cancer cells can produce molecules called immune checkpoint inhibitors that bind to and inhibit the activity of T cells, preventing them from recognizing and attacking cancer cells (Lao et al. 2022 ).

Additionally, cancer cells can recruit immune cells that promote immune suppression, such as regulatory T cells and myeloid-derived suppressor cells, which further dampen the immune response against cancer (Brody 2016 ). Cancer cells can also evade the immune system by changing the location of the antigens within the cell, called the abscopal effect, where the cancer cells move the antigens to the inside of the cell, making them invisible to the immune system (Beatty and Gladney 2015 ; Alfonso et al. 2020 ). Recent research has shown that targeting the mechanisms of antigen presentation and immune escape can be an effective strategy for treating cancer. For example, drugs that block immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1, have been approved for use in several types of cancer and have shown promising results in clinical trials (Seidel et al. 2018 ; Rotte 2019 ). In a snapshot, antigen presentation plays a crucial role in the ability of the immune system to identify and target cancer cells. Understanding the mechanisms of antigen presentation and immune escape is crucial for developing effective cancer immunotherapies.

Immune system and cancer

The immune system plays a crucial role in the development and progression of cancer (Gonzalez et al. 2018 ). Cancer cells develop from normal cells and can evade the immune system through various mechanisms; one of them is a process known as an immune escape. The immune system can recognize and target cancer cells through immunosurveillance. This process involves specialized immune cells, such as T cells and natural killer cells, that can detect and destroy cancer cells (Marcus et al. 2014 ; Gonzalez et al. 2018 ). The immune system also plays a role in shaping the microenvironment of the tumour. Tumour-associated macrophages, dendritic cells, and Treg cells are some of the cells found in the tumour microenvironment and play a role in cancer progression (Anderson and Simon 2020 ). Tumour-associated macrophages and dendritic cells can promote cancer cell growth by secreting factors that promote angiogenesis and inhibiting T cell activity. On the other hand Treg cells can suppress the immune response against cancer by inhibiting the activation and proliferation of T cells (Baay et al. 2011 ).

Another important mechanism in cancer progression is the ability of cancer cells to evade the immune system by downregulating or losing the expression of the proteins recognized by the immune cells as antigens (Dhatchinamoorthy et al. 2021 ). Recent research has shown that targeting the mechanisms of antigen presentation and immune escape can be an effective strategy for treating cancer. For example, drugs that block immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1, have been approved for use in several types of cancer and have shown promising results in clinical trials (Wojtukiewicz et al. 2021 ; Xiang et al. 2022 ; Sové et al. 2022 ). The immune system plays a crucial role in the development and progression of cancer. Understanding the mechanisms of immunosurveillance, immune escape, and the immune system's role in shaping the tumour microenvironment is crucial for developing effective cancer immunotherapies. Immune-based therapies, such as cancer vaccines and checkpoint inhibitors, have shown great promise in treating cancer and are expected to play a significant role in cancer treatment.

Immune checkpoints and immune evasion in cancer

Cancer immune evasion refers to the ability of cancer cells to evade detection and destruction by the immune system (Vinay et al. 2015 ). This complex process involves multiple mechanisms that enable cancer cells to evade the immunosurveillance mechanisms of the body (Messerschmidt et al. 2016 ).

Immune checkpoints are molecules or pathways that regulate the activation and function of the immune system. Immune checkpoint inhibitors are a class of drugs that block the function of these checkpoints, thereby enhancing the immune response against cancer cells (He and Xu 2020 ). One of the most well-known immune checkpoint pathways is the CTLA-4 pathway (Buchbinder and Desai 2016 ). CTLA-4 is a protein expressed on the surface of T cells that acts as an inhibitory receptor, blocking the activation and proliferation of T cells (Parry et al. 2005 ). Anti-CTLA-4 therapies, such as ipilimumab, act by binding to and blocking the function of CTLA-4, thereby enhancing the immune response against cancer cells (Callahan et al. 2010 ). Another critical immune checkpoint pathway is the PD-1/PD-L1. PD-1 is a protein expressed on the surface of T cells that interacts with PD-L1, which is expressed on the surface of cancer cells. This interaction blocks the activation and proliferation of T cells, allowing cancer cells to evade the immune response (Han et al. 2020 ). Anti-PD-1/PD-L1 treatments, such as nivolumab and pembrolizumab, work by binding to and inhibiting the interaction of PD-1 and PD-L1, increasing the immune response against cancer cells (Fessas et al. 2017 ) (Fig.  1 ).

figure 1

Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1 drugs, enhance the immune response against cancer by blocking immune checkpoint pathways. Other checkpoint pathways, such as LAG-3 and TIGIT, are being investigated as potential targets for cancer therapy and may have synergistic effects when combined with other checkpoint inhibitors

Other immune checkpoint pathways, such as LAG-3 and TIGIT, are also being investigated as potential targets for cancer therapy. LAG-3 (lymphocyte activation gene 3) is a protein that binds to MHC class II molecules and regulates T cell activation and exhaustion (Ge et al. 2021 ; Huo et al. 2022 ). TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a protein that binds to both T cells and immune cells and regulates T cell activation and function. Preclinical research has demonstrated a significant impact of these pathways, and clinical trials are currently being conducted to explore their potential as therapeutic cancer targets (Yue et al. 2022 ). LAG-3 and TIGIT have a unique mechanism of action compared to other immune checkpoint inhibitors, such as PD-1 and CTLA-4, and may have a synergistic effect when combined with these drugs. This could potentially lead to improved efficacy and reduced side effects. In preclinical studies, TIGIT and LAG-3 inhibitors are effective in combination with PD-1 inhibitors in various cancer models, such as melanoma, lung cancer, and ovarian cancer (De Sousa et al. 2018 ; Seidel et al. 2018 ; Willsmore et al. 2021 ).

Antigen presentation in cancer

Antigen processing and presentation are crucial mechanisms by which the immune system recognizes and targets cancer cells. This process involves the recognition of cancer cell-associated antigens by APCs and their subsequent presentation on the surface of these cells in a form that can be recognized by T cells (Mpakali and Stratikos 2021 ). The antigen processing and presentation process begins with the internalization of cancer cell-associated antigens by APCs (Blum et al. 2013 ; Lee et al. 2020 ). Once inside the cell, the antigens are degraded into small peptides by a complex of enzymes called the proteasome. These peptides are then transported to the endoplasmic reticulum, complex with MHC molecules (Rock et al. 2010 ). MHC molecules are specialized proteins that are essential for the recognition of antigens by T cells. There are two main types of MHC molecules: MHC class I and MHC class II. MHC class I molecules are expressed on the surface of all nucleated cells, including cancer cells, and present peptides derived from intracellular antigens. On the other hand, MHC class II molecules are expressed primarily on the surface of APCs and present peptides derived from extracellular antigens (Wieczorek et al. 2017 ).

The MHC-peptide complex is then transported to the cell surface, where it can be recognized by T cells. T cells have specialized T cell receptors (TCRs) that recognize the MHC-peptide complex (Alberts et al. 2002 ). When a T cell recognizes a cancer cell-associated antigen displayed on an APC, it becomes activated and begins to divide and differentiate into specialized cells that can attack and destroy the cancer cells (Kunimasa and Goto 2020 ). However, cancer cells can evade the immune system by downregulating or losing the expression of the proteins recognized by the immune cells as antigens. This can happen by mutations in the cancer cells that affect the expression of these proteins or by the cancer cells creating an immunosuppressive microenvironment that prevents the immune cells from recognizing and attacking the cancer cells (Beatty and Gladney 2015 ) (Fig.  2 ). Many reports have shown that cancer cells can also evade the immune system by altering their ability to process and present antigens. For example, some cancer cells can downregulate the expression of MHC molecules, making them invisible to the immune system (Mittal et al. 2014 ; Reeves and James 2017 ; Kulkarni et al. 2019 ). Cancer cells can also interfere with the activity of the proteasome, thereby preventing the degradation of cancer cell-associated antigens (Mittal et al. 2014 ; Reeves and James 2017 ; Kulkarni et al. 2019 ).

figure 2

APCs internalize cancer cell-associated antigens and degrade them into small peptides, which are then presented on the surface of APCs as MHC-peptide complexes that can be recognized by T cells. Cancer cells can evade the immune system by downregulating or losing the expression of antigen proteins, altering their ability to process and present antigens, or creating an immunosuppressive microenvironment

MHC 1 in antigen presentation

Major histocompatibility complex class I (MHC-I) molecules play a critical role in antigen presentation. These molecules are expressed on the surface of all nucleated cells, including cancer cells, and are responsible for the presentation of peptides derived from intracellular antigens to CD8 + T cells, also known as cytotoxic T cells (van den Elsen 2011 ; Wang et al. 2019 ). The MHC-I molecule comprises two main components: the heavy chain, encoded by the HLA gene, and the beta-2-microglobulin (β2m), a non-polymorphic component. The heavy chain comprises three main domains: the α1, α2, and α3. The α1 and α2 domains bind the MHC-I molecule to the peptide, while the α3 domain is responsible for interacting with the CD8 T-cell receptor (Cruz-Tapias et al. 2013 ). The process of MHC-I presentation begins with the internalization of antigens by the cell. Once an antigen enters a cell, a group of enzymes called the proteasome breaks it down into a little peptide.

Peptide loading delivers these peptides to the endoplasmic reticulum, where they interact with the MHC-I molecule. The MHC-I-peptide complex is then transported to the cell surface, where it can be recognized by CD8 + T cells (Hewitt 2003 ). The binding of the peptide to the MHC-I molecule is mediated by the peptide-binding groove, which is composed of the α1 and α2 domains. The peptide-binding groove can only bind to peptides that are 8–10 amino acids long. Once the peptide is bound to the MHC-I molecule, it is transported to the cell surface (Fig.  3 ) (Zacharias and Springer 2004 ). Downregulating or removing proteins that express antigens allows cancer cells to evade the immune system. The ability of cancer cells to process and present antigens on MHC-I molecules can change if they develop an immunosuppressive microenvironment or experience protein expression mutations. Understanding the mechanisms of MHC-I presentation in cancer is crucial for developing effective cancer immunotherapies.

figure 3

MHC-I antigen presentation. MHC-I molecules on the cell surface present intracellular antigen peptides to CD8 + T cells. Cancer cells can evade the immune system by downregulating antigen expression or altering antigen processing and presentation on MHC-I

Immunopeptidome and cancer

The immunopeptidome is the set of peptides presented by MHC molecules on the surface of cells (Yewdell 2022a ). These peptides are derived from the degradation of intracellular proteins and are essential for recognizing cancer cells by the immune system. The study of the immunopeptidome, also known as peptidomics, has revealed insights into the mechanisms of cancer immune evasion and has potential applications in cancer diagnosis and treatment (Synowsky et al. 2017 ; Yewdell 2022b ). One of the critical roles of the immunopeptidome in cancer is its ability to identify unique peptides specific to cancer cells. These cancer-specific peptides, also known as neoantigens, can be used to develop personalized cancer vaccines targeting the unique mutations in an individual's cancer. Neoantigen-based vaccines have shown promising results in clinical trials and are expected to play an essential role in the future of cancer immunotherapy (D’Amico et al. 2022 ; Ouspenskaia et al. 2022 ). Another essential role of the immunopeptidome in cancer is its ability to provide insights into the mechanisms of cancer immune evasion. The study of the immunopeptidome can reveal which proteins are being presented by MHC molecules and which are not, providing insight into the mechanisms of cancer immune evasion (León-Letelier et al. 2022 ). The immunopeptidome can also provide valuable information for cancer diagnosis, such as immunopeptidome-based cancer diagnostics, tumour-associated antigen (TAA) testing, MHC class I tetramer staining and mass spectrometry-based peptidomics. Additionally, the study of the immunopeptidome can provide insights into the progression of cancer and the response to treatment by monitoring changes in the peptides presented by MHC molecules (Dersh et al. 2021 ).

Tumor antigen expression, presentation and control

The control of tumour antigen expression and presentation is a critical aspect of cancer biology that significantly impacts the immune system's ability to recognize and target cancer cells (Whiteside 2006 ). Tumours evade immune recognition through various mechanisms, such as the downregulation of antigens recognized by immune cells, the creation of an immunosuppressive microenvironment, and interaction with immune checkpoint pathways. Tumour antigens are molecules expressed on the surface of cancer cells and recognized by the immune system as foreign (Fig.  4 ).

figure 4

Tumors can evade detection and destruction by the immune system, thereby allowing for uncontrolled growth and progression. This process is referred to as immune evasion and is a complex mechanism that involves the downregulation or loss of antigens recognized by immune cells, the creation of an immunosuppressive microenvironment, and interaction with immune checkpoint pathways

Cancer cells can regulate tumour antigen expression via epigenetics, like DNA structure changes (methylation, histone modification). They can also reduce antigen expression, hide from the immune system, and inhibit antigen-presenting cells/T cells (TGF-beta, IL-10) from suppressing immune response.(Gibney and Nolan 2010 ). Another mechanism by which cancer cells can control the expression of tumour antigens is through the manipulation of the proteasome and the MHC molecules (Boulpicante et al. 2020 ). The proteasome is a complex of enzymes responsible for degrading intracellular proteins, including tumour antigens, into peptides that MHC molecules can present. Cancer cells can interfere with the activity of the proteasome, thereby preventing the degradation of cancer cell-associated antigens and avoiding the presentation of the antigens on the MHC molecules (Chen et al. 2022 ). Cancer cells can also downregulate the expression of MHC molecules, thus making them invisible to the immune system and avoiding antigen presentation, or manipulate the structure of the MHC molecules, such as altering the peptide binding affinity, which can prevent the presentation of the cancer-associated antigens (Hewitt 2003 ; Rock et al. 2010 ; Blum et al. 2013 ).

Epigenetic modulation of immunotherapy

One mechanism by which cancer cells can control the expression of tumour antigens is through epigenetic regulation. Epigenetics refers to the regulation of gene expression through changes in the structure of DNA, such as methylation and histone modification, rather than changes in the genetic code itself (Gibney and Nolan 2010 ). Cancer cells can alter the epigenetic landscape to downregulate the expression of tumour antigens, making them invisible to the immune system. Cancer cells can also secrete factors that inhibit the activity of antigen-presenting cells and T cells, such as TGF-beta and IL-10, which further suppress the immune response (Thepmalee et al. 2018 ). Epigenetic modulation of antitumor immunity has been an active area of research in recent years and has been found to have potential applications in cancer immunotherapy (Gibney and Nolan 2010 ). Cancer cells' manipulation of the epigenetic landscape has been shown to play a critical role in suppressing the immune response against cancer. By targeting these mechanisms, it is possible to improve the efficacy of cancer immunotherapy (Liu et al. 2022a ). One way in which epigenetic modulation can be targeted is through the use of histone deacetylase inhibitors (HDACis). HDACis are a class of drugs that inhibit the activity of histone deacetylases, enzymes that remove acetyl groups from histones, leading to the repression of gene expression. HDACis have been shown to enhance the maturation of dendritic cells and increase the presentation of tumour antigens, thus enhancing the immune response against cancer (Gryder et al. 2012 ).

Another way to target epigenetic modulation is through DNA methyltransferase inhibitors (DNMTis) (Hu et al. 2021 ). DNMTis are a class of drugs that inhibit the activity of DNA methyltransferases, enzymes that add methyl groups to DNA, leading to the repression of gene expression. DNMTis have been shown to increase the expression of genes involved in the immune response, such as MHC molecules, and modulate the expression of genes involved in immune evasions, such as PD-L1 (Dan et al. 2019 ) (Fig.  5 ). The combination therapies that combine epigenetic modulation with other immunotherapeutic strategies, such as checkpoint inhibitors, have also yielded promising results in clinical trials. For example, combining HDACis with PD-1/PD-L1 inhibitors has enhanced the response to treatment in multiple cancer types (Mazzone et al. 2017 ; Liu et al. 2022b ).

figure 5

Diagram illustrating the epigenetic regulation of chromatin accessibility and gene expression in cells. Nucleosomes, formed by DNA wrapped around histone octamers, are depicted as blue cylinders. Epigenetic modifications are depicted as dynamic interactions between chromatin components and enzymes, including histone methylation/demethylation, histone acetylation/deacetylation, and DNA methylation. Chromatin remodelling also plays a role in regulating gene expression

It is important to note that while the use of these epigenetic modulation therapies has shown promising results in preclinical and clinical studies, more research is needed to fully understand the mechanisms of action and optimal use in the clinical setting. Further research is also needed to understand these therapies' potential side effects and long-term safety.

Antigen presentation machinery components, modulation and their defects

The antigen processing machinery (APM) plays a critical role in developing an effective antitumor immune response (Maggs et al. 2021 ). The APM is a group of cellular structures and molecules responsible for processing and presenting APCs to T cells. Defects in the APM can compromise the ability of the immune system to recognize and respond to cancer cells, leading to the development of tumours that evade destruction by the immune system (Mpakali and Stratikos 2021 ). The major components of the APM include proteasomes, which are responsible for the degradation of proteins into peptides; TAP (transporter associated with antigen processing), which transports the peptides from the cytosol to the endoplasmic reticulum (ER); and MHC (major histocompatibility complex) molecules, which present the peptides on the surface of APCs to T cells. A growing body of evidence suggests that defects in the APM can contribute to cancer development. For example, mutations in the genes encoding the proteasomes or TAP can reduce the ability to generate peptides that can be presented on MHC molecules (Reiman et al. 2007 ). This can limit the ability of the immune system to recognize and respond to cancer cells. Additionally, defects in MHC molecules can result in a decreased ability to mount an immune response against certain infections and cancer (Charles et al. 2001 ; Dassa 2003 ).

Cancer cells can modulate antigen presentation in several ways to evade recognition and destruction by the immune system. Cancer cells can do this by deregulation of MHC molecules; Cancer cells can reduce the expression of MHC molecules on their surface, making them less visible to T cells and harder to target. Disruption of antigen processing; Cancer cells can interfere with the normal processing of antigens within the cell, making it harder for APCs to present them on MHC molecules. Production of immunosuppressive molecules; Cancer cells can produce molecules that suppress the immune response, such as TGF-beta and IDO, making it harder for T cells to recognize and attack cancer cells. Recruitment of immune-suppressive cells; Cancer cells can recruit immune cells that suppress the immune response, such as Tregs and MDSCs, to the tumour microenvironment (Vinay et al. 2015 ; Parcesepe et al. 2016 ; Mergener and Peña-Llopis 2022 ).

Defects in any of these components can result in a compromised immune response. For example, mutations in MHC molecules can result in a condition called MHC deficiency, which leads to a decreased ability to mount an immune response against certain infections. Similarly, TCR defects can result in T cell dysfunction and increased susceptibility to infections. Defects in the antigen presentation machinery can significantly impact the immune system's ability to recognize and respond to cancer cells, and understanding these defects can inform the development of new immunotherapies for cancer (Mpakali and Stratikos 2021 ). The development of immunotherapies for cancer has been a promising approach to targeting tumours that evade destruction by the immune system. These therapies aim to re-activate the patient's immune system to recognize and attack cancer cells. This can include checkpoint inhibitors, which block the immune-suppressive signals emitted by cancer cells and allow T cells to recognize and attack the tumour, and CAR T-cell therapy, which genetically modifies a patient's T cells to recognize and attack cancer cells (Filley et al. 2018 ).

Neoantigens in cancer immunotherapy

Neoantigens are a class of tumour-specific antigens generated by genetic mutations in cancer cells. They are not present in normal cells and, thus, represent a unique target for cancer immunotherapy. Identifying and characterising neoantigens have led to the development of new immunotherapeutic strategies for cancer treatment (Zhu and Liu 2021 ). The process of neoantigen identification begins with the sequencing of a patient's tumour and normal DNA (Zhu and Liu 2021 ). Algorithms are then used to identify potential neoantigens based on their predicted binding to MHC molecules and their potential to be presented on the cell surface. These potential neoantigens are further validated through functional assays, such as T-cell assays, to confirm their ability to elicit a T-cell response (Garcia-Garijo et al. 2019 ; Zaidi et al. 2020 ). Once identified, neoantigens can be used to develop personalized cancer vaccines (Blass and Ott 2021 ). These vaccines can target specific mutations in an individual's tumour and stimulate an immune response against cancer cells. The vaccines can be either ex vivo, where T cells are extracted from the patient, genetically modified to recognize the neoantigens, and then re-infused back into the patient or in vivo, where the patient is administered with the neoantigen peptides (Xie et al. 2023 ).

Recent clinical trials have demonstrated the safety and efficacy of personalized neoantigen cancer vaccines (Fritah et al. 2022 ). The results have shown that these vaccines can induce antitumor T-cell responses and result in durable clinical responses in a subset of patients with advanced cancer. Additionally, a combination of neoantigen vaccine with checkpoint inhibitors has shown to be more effective in inducing antitumor T-cell response and, in some cases, led to complete remission of the disease (Liao and Zhang 2021 ). Furthermore, the identification of neoantigens has also led to the development of neoantigen-targeting T-cell therapies, such as CAR-T cell therapy. In this approach, T cells are genetically modified to express a CAR specific for a neoantigen and then re-infused back into the patient. These therapies have shown effective in inducing long-lasting responses in patients with advanced cancer (Wang and Cao 2020 ).

The antigen processing and presentation mechanisms play a critical role in the immune system's recognition and targeting of cancer cells. Cancer cells can avoid immune detection by downregulating or losing the expression of proteins recognised as antigens, creating an immunosuppressive microenvironment, and altering their ability to process and present antigens. The study of the immunopeptidome, or peptidomics, has provided insights into the mechanisms of cancer immune evasion and has potential applications in cancer diagnosis and treatment. One mechanism by which cancer cells can control the expression of tumour antigens is through epigenetic regulation, such as methylation and histone modification; cancer cells can alter the epigenetic landscape to downregulate the expression of tumour antigens, making them invisible to the immune system. Additionally, cancer cells can manipulate the microenvironment, interfere with the activity of the proteasome and MHC molecules, and downregulate the expression of MHC molecules to avoid the presentation of antigens. Recent advances in cancer genomics and molecular biology have allowed the identification of unique antigens present in cancer cells but not in normal cells, known as "neoantigens." These neoantigens can be used to develop cancer vaccines and CAR-T cell therapy that target the specific mutations present in an individual's tumour, leading to the re-activation of the patient's immune system to recognize and attack cancer cells. Targeting the epigenetic mechanisms that cancer cells use to evade the immune system can improve cancer immunotherapy, such as using HDACis, DNMTis, and combination therapies. However, it's important to note that more research is needed to fully understand the mechanisms of action and optimal use of these therapies in the clinical setting. In snapshot, controlling tumour antigen expression and presentation is a critical aspect of cancer biology that significantly impacts the immune system's ability to recognize and target cancer cells. Understanding these mechanisms is crucial for developing effective cancer immunotherapies that target the mechanisms of antigen expression and presentation in cancer cells and for a better understanding of the epigenetic modulation of antitumor immunity for improved cancer immunotherapy.

Data availability

All data generated or analysed during this study are included in this published article.

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Conceptualization, methodology, writing original draft preparation, AK, MO, NM. writing—review and editing, WB. supervision, MB. All authors have read and agreed to the final version of the manuscript.

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Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233, Gdansk, Poland

Anoop Kallingal, Mateusz Olszewski, Natalia Maciejewska, Wioletta Brankiewicz & Maciej Baginski

Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

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Kallingal, A., Olszewski, M., Maciejewska, N. et al. Cancer immune escape: the role of antigen presentation machinery. J Cancer Res Clin Oncol 149 , 8131–8141 (2023). https://doi.org/10.1007/s00432-023-04737-8

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DOI : https://doi.org/10.1007/s00432-023-04737-8

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Direct antigen presentation is the canonical pathway of cytomegalovirus CD8 T-cell priming regulated by balanced immune evasion ensuring a strong antiviral response

Affiliations.

  • 1 Institute for Virology and Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 2 Institute of Virology, Medical Faculty, University of Bonn, Bonn, Germany.
  • 3 Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany.
  • 4 Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • PMID: 38149242
  • PMCID: PMC10749961
  • DOI: 10.3389/fimmu.2023.1272166

CD8 T cells are important antiviral effectors in the adaptive immune response to cytomegaloviruses (CMV). Naïve CD8 T cells can be primed by professional antigen-presenting cells (pAPCs) alternatively by "direct antigen presentation" or "antigen cross-presentation". In the case of direct antigen presentation, viral proteins are expressed in infected pAPCs and enter the classical MHC class-I (MHC-I) pathway of antigen processing and presentation of antigenic peptides. In the alternative pathway of antigen cross-presentation, viral antigenic material derived from infected cells of principally any cell type is taken up by uninfected pAPCs and eventually also fed into the MHC class-I pathway. A fundamental difference, which can be used to distinguish between these two mechanisms, is the fact that viral immune evasion proteins that interfere with the cell surface trafficking of peptide-loaded MHC-I (pMHC-I) complexes are absent in cross-presenting uninfected pAPCs. Murine cytomegalovirus (mCMV) models designed to disrupt either of the two presentation pathways revealed that both are possible in principle and can substitute each other. Overall, however, the majority of evidence has led to current opinion favoring cross-presentation as the canonical pathway. To study priming in the normal host genetically competent in both antigen presentation pathways, we took the novel approach of enhancing or inhibiting direct antigen presentation by using recombinant viruses lacking or overexpressing a key mCMV immune evasion protein. Against any prediction, the strongest CD8 T-cell response was elicited under the condition of intermediate direct antigen presentation, as it exists for wild-type virus, whereas the extremes of enhanced or inhibited direct antigen presentation resulted in an identical and weaker response. Our findings are explained by direct antigen presentation combined with a negative feedback regulation exerted by the newly primed antiviral effector CD8 T cells. This insight sheds a completely new light on the acquisition of viral immune evasion genes during virus-host co-evolution.

Keywords: CD8 T cell response; antigen cross-presentation; antigen presentation; antigen presenting cell (APC); m152/gp40; murine cytomegalovirus (mCMV).

Copyright © 2023 Büttner, Becker, Fink, Brinkmann, Holtappels, Reddehase and Lemmermann.

  • Antigen Presentation*
  • Antiviral Agents
  • CD8-Positive T-Lymphocytes
  • Cytomegalovirus
  • Immune Evasion
  • Muromegalovirus*
  • Viral Proteins

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IMAGES

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  1. A guide to antigen processing and presentation

    Antigen processing and presentation are the cornerstones of adaptive immunity. B cells cannot generate high-affinity antibodies without T cell help. CD4 + T cells, which provide such help, use...

  2. Antigen presentation

    Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.. Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment can be recognized by a T-cell receptor.

  3. Antigen Processing and Presentation

    Figure 1. The MHC class I antigen-presentation pathway. MHC class I presentation MHC class I molecules are expressed by all nucleated cells. MHC class I molecules are assembled in the endoplasmic reticulum (ER) and consist of two types of chain - a polymorphic heavy chain and a chain called β2-microglobulin.

  4. Antigen processing

    Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways.

  5. Antigen Processing and Presentation

    This process of antigen presentation allows T cells to "see" what proteins are present in the body and to form an adaptive immune response against them. In this article, we shall discuss antigen processing, presentation, and recognition by T cells. Antigen Presentation

  6. 20.3E: Antigen-Presenting Cells

    Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens, then present them to naive T-cells. The basis of adaptive immunity lies in the capacity of immune cells to distinguish between the body's own cells and infectious pathogens. The host's cells express ...

  7. Antigen presentation in cancer

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  8. Antigen Presentation

    Antigen presentation, activation of both CD4+ cells (such as TH1 and TH17s) and CD8+ T cells, increases in the inflammatory cytokines, IL-6, IL-12, TNFα, and IFNγ, and NFκB activation, in addition to decreased pro-apoptotic proteins such as caspase 8 and 10, lead to enhanced immune cell survival and activation of pro-inflammatory mechanisms [116...

  9. Pathways of Antigen Processing

    Conversion of antigens from pathogens or transformed cells into MHC-I and MHC-II-bound peptides is critical for mounting protective T cell responses, and similar processing of self proteins is necessary to establish and maintain tolerance.

  10. 15.4M: Antigen Presentation

    15.4M: Antigen Presentation. Antigens are macromolecules that elicit an immune response in the body. Antigens can be proteins, polysaccharides, conjugates of lipids with proteins (lipoproteins) and polysaccharides (glycolipids). Most of this page will describe how protein antigens are presented to the immune system.

  11. Antigen Presentation

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  12. Genetics of antigen processing and presentation

    Processing of the antigen, to peptides or other moieties, requires other sets of molecules. For classical class I, this includes TAP peptide transporters, proteasome components and Tapasin, genes which are encoded within the MHC. Similarly, HLA-DO and -DM, which influence presentation by HLA class II molecules, are encoded in the MHC region.

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    pathway. This process requires the chaperone HLA-DM, and, in the case of B cells, the HLA-DOmolecule. MHC class II molecules loaded with foreign peptide are then transported to the cell membrane to present their cargo to CD4+ T cells. Thereafter, the process of antigen presentation by means of MHC class II molecules basically

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    Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs.

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    Identify the cells that are antigen-presenting cells; Describe the process of antigen processing and presentation with MHC I and MHC II; As discussed in Cellular Defenses, major histocompatibility complex (MHC) molecules are expressed on the surface of healthy cells, identifying them as normal and "self" to natural killer (NK) cells. MHC ...

  19. 12.2: Antigens, Antigen Presenting Cells, and Major Histocompatibility

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    Antigen processing refers to the intracellular mechanisms by which antigens are degraded into smaller peptide fragments. This process occurs within antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells.

  22. Antigen processing and presentation: Cytosolic and Endocytic pathway

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