explain the process of antigen presentation

BiteSized Immunology: Systems & Processes

Antigen Processing and Presentation

In order to be capable of engaging the key elements of adaptive immunity (specificity, memory, diversity, self/nonself discrimination), antigens have to be processed and presented to immune cells. Antigen presentation is mediated by MHC class I molecules , and the class II molecules found on the surface of antigen-presenting cells (APCs) and certain other cells.

MHC class I and class II molecules are similar in function: they deliver short peptides to the cell surface allowing these peptides to be recognised by CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The difference is that the peptides originate from different sources – endogenous, or intracellular , for MHC class I; and exogenous, or extracellular for MHC class II. There is also so called cross-presentation in which exogenous antigens can be presented by MHC class I molecules. Endogenous antigens can also be presented by MHC class II when they are degraded through autophagy.

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. The heavy chain is stabilised by the chaperone calnexin , prior to association with the β2-microglobulin. Without peptides, these molecules are stabilised by chaperone proteins : calreticulin, Erp57, protein disulfide isomerase (PDI) and tapasin. The complex of TAP, tapasin, MHC class I, ERp57 and calreticulin is called the peptide-loading complex (PLC). Tapasin interacts with the transport protein TAP (transporter associated with antigen presentation) which translocates peptides from the cytoplasm into the ER. Prior to entering the ER, peptides are derived from the degradation of proteins, which can be of viral- or self origin. Degradation of proteins is mediated by cytosolic- and nuclear proteasomes, and the resulting peptides are translocated into the ER by means of TAP. TAP translocates peptides of 8 –16 amino acids and they may require additional trimming in the ER before binding to MHC class I molecules. This is possibly due to the presence of ER aminopeptidase (ERAAP) associated with antigen processing.

It should be noted that 30–70% of proteins are immediately degraded after synthesis (they are called DRiPs – defective ribosomal products, and they are the result of defective transcription or translation). This process allows viral peptides to be presented very quickly – for example, influenza virus can be recognised by T cells approximately 1.5 hours post-infection. When peptides bind to MHC class I molecules, the chaperones are released and peptide–MHC class I complexes leave the ER for presentation at the cell surface. In some cases, peptides fail to associate with MHC class I and they have to be returned to the cytosol for degradation. Some MHC class I molecules never bind peptides and they are also degraded by the ER-associated protein degradation (ERAD) system.

There are different proteasomes that generate peptides for MHC class-I presentation: 26S proteasome , which is expressed by most cells; the immunoproteasome, which is expressed by many immune cells; and the thymic-specific proteasome expressed by thymic epithelial cells.

Antigen presentation

On the surface of a single cell, MHC class I molecules provide a readout of the expression level of up to 10,000 proteins. This array is interpreted by cytotoxic T lymphocytes and Natural Killer cells, allowing them to monitor the events inside the cell and detect infection and tumorigenesis.

MHC class I complexes at the cell surface may dissociate as time passes and the heavy chain can be internalised. When MHC class I molecules are internalised into the endosome, they enter the MHC class-II presentation pathway. Some of the MHC class I molecules can be recycled and present endosomal peptides as a part of a process which is called cross-presentation .

The usual process of antigen presentation through the MHC I molecule is based on an interaction between the T-cell receptor and a peptide bound to the MHC class I molecule. There is also an interaction between the CD8+ molecule on the surface of the T cell and non-peptide binding regions on the MHC class I molecule. Thus, peptide presented in complex with MHC class I can only be recognised by CD8+ T cells. This interaction is a part of so-called ‘three-signal activation model’, and actually represents the first signal. The next signal is the interaction between CD80/86 on the APC and CD28 on the surface of the T cell, followed by a third signal – the production of cytokines by the APC which fully activates the T cell to provide a specific response.

MHC class I polymorphism

Human MHC class I molecules are encoded by a series of genes – HLA-A, HLA-B and HLA-C (HLA stands for ‘Human Leukocyte Antigen’, which is the human equivalent of MHC molecules found in most vertebrates). These genes are highly polymorphic, which means that each individual has his/her own HLA allele set. The consequences of these polymorphisms are differential susceptibilities to infection and autoimmune diseases that may result from the high diversity of peptides that can bind to MHC class I in different individuals. Also, MHC class I polymorphisms make it virtually impossible to have a perfect tissue match between donor and recipient, and thus are responsible for graft rejection.

MHC class II presentation

MHC class II molecules are expressed by APCs, such as dendritic cells (DC), macrophages and B cells (and, under IFNγ stimuli, by mesenchymal stromal cells, fibroblasts and endothelial cells, as well as by epithelial cells and enteric glial cells). MHC class II molecules bind to peptides that are derived from proteins degraded in the endocytic pathway. MHC class II complexes consists of α- and β-chains that are assembled in the ER and are stabilised by invariant chain (Ii). The complex of MHC class II and Ii is transported through the Golgi into a compartment which is termed the MHC class II compartment (MIIC). Due to acidic pH, proteases cathepsin S and cathepsin L are activated and digest Ii, leaving a residual class II-associated Ii peptide (CLIP) in the peptide-binding groove of the MHC class II. Later, the CLIP is exchanged for an antigenic peptide derived from a protein degraded in the endosomal pathway. This process requires the chaperone HLA-DM, and, in the case of B cells, the HLA-DO molecule. 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 follows the same pattern as for MHC class I presentation.

As opposed to MHC class I, MHC class II molecules do not dissociate at the plasma membrane. The mechanisms that control MHC class II degradation have not been established yet, but MHC class II molecules can be ubiquitinised and then internalised in an endocytic pathway.

MHC class II polymorphism

Like the MHC class I heavy chain, human MHC class II molecules are encoded by three polymorphic genes: HLA-DR, HLA-DQ and HLA-DP. Different MHC class II alleles can be used as genetic markers for several autoimmune diseases, possibly owing to the peptides that they present.

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Antigen Processing and Presentation

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Original Author(s): Antonia Round Last updated: 17th July 2023 Revisions: 9

• 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.

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.

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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20.3E: Antigen-Presenting Cells

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Antigen presentation is a process by which immune cells capture antigens and then enable their recognition by T cells.

Learning Objectives

• Describe the role of antigen-presenting cells
• The host’s cells express “self” antigens that identify them as such. These antigens are different from those in bacteria (“non-self” antigens) and in virus-infected host cells (“missing-self”).
• Antigen presentation consists of pathogen recognition, phagocytosis of the pathogen or its molecular components, processing of the antigen, and then presentation of the antigen to naive T cells.
• The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the major histocompatibility complex (MHC), also known in humans as human leukocyte antigen (HLA).
• Helper T cells recieve antigens from MHC II on an APC, while cytotoxic T cells recieve antigens from MHC I. Helper T cells present their antigen to B cells as well.Dendritic cells, B cells, and macrophages play a major role in the innate response, and are the primary antigen-presenting cells (APC).
• APCs use toll-like receptors to identify PAMPS and DAMPs, which are signs of an infection and may be processed into antigen peptides if phagocytized. Most APCs cannot tell the difference between different types of antigens like B and T cells can.
• damage-associated molecular pattern : Protein or nucleic acid based signs of pathogen induced damage. Protein DAMPs may be phagocytized and processed for antigen presentation.
• cytotoxic : A population of T cells specialized for inducing the deaths of other 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 “self” antigens that identify them as belonging to the self. These antigens are different from those in bacteria (“non-self” antigens) or in virally-infected host cells (“missing-self”). Antigen presentation broadly consists of pathogen recognition, phagocytosis of the pathogen or its molecular components, processing of the antigen, and then presentation of the antigen to naive (mature but not yet activated) T cells. The ability of the adaptive immune system to fight off pathogens and end an infection depends on antigen presentation.

Antigen Presenting Cells

Antigen Presenting Cells (APCs) are cells that capture antigens from within the body, and present them to naive T-cells. Many immune system cells can present antigens, but the most common types are macrophages and dendritic cells, which are two types of terminally differentiated leukocytes that arise from monocytes. Both of these APCs perform many immune functions that are important for both innate and adaptive immunity, such as removing leftover pathogens and dead neutrophils after an inflammatory response. Dendritic cells (DCs) are generally found in tissues that have contact with the external environment (such as the skin or respiratory epithelium) while macrophages are found in almost all tissues. Some types of B cells may also present antigens as well, though it is not their primary function.

APCs phagocytize exogenous pathogens such as bacteria, parasites, and toxins in the tissues and then migrate, via chemokine signals, to lymph nodes that contain naive T cells. During migration, APCs undergo a process of maturation in which they digest phagocytized pathogens and begin to express the antigen in the form of a peptide on their MHC complexes, which enables them to present the antigen to naive T cells. The antigen digestion phase is also called “antigen processing,” because it prepares the antigens for presentation. This MHC:antigen complex is then recognized by T cells passing through the lymph node. Exogenous antigens are usually displayed on MHC Class II molecules, which interact with CD4+ helper T cells.

This maturation process is dependent on signaling from other pathogen-associated molecular pattern (PAMP) molecules (such as a toxin or component of a cell membrane from a pathogen) through pattern recognition receptors (PRRs), which are received by Toll-like receptors on the DC’s body. They may also recognize damage-associated molecular pattern (DAMP) molecules, which include degraded proteins or nucleic acids released from cells that undergo necrosis. PAMPs and DAMPS are not technically considered antigens themselves, but instead are signs of pathogen presence that alert APCs through Toll-like receptor binding. However if a DC phagocytzes a PAMP or DAMP, it could be used as an antigen during antigen presentation. APCs are unable to distinguish between different types of antigens themselves, but B and T cells can due to their specificity.

Antigen Presentation

T cells must be presented with antigens in order to perform immune system functions. The T cell receptor is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the MHC complexes on APCs, also known in humans as Human leukocyte antigen (HLA).

Several different types of T cell can be activated by APCs, and each type of T cell is specially equipped to deal with different pathogens, whether the pathogen is bacterial, viral or a toxin. The type of T cell activated, and therefore the type of response generated, depends on which MHC complex the processed antigen-peptide binds to.

MHC Class I molecules present antigen to CD8+ cytotoxic T cells, while MHC class II molecules present antigen to CD4+ helper T cells. With the exception of some cell types (such as erythrocytes), Class I MHC is expressed by almost all host cells. Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a population of T cells that are specialized for inducing the death of other cells. Recognition of antigenic peptides through Class I by CTLs leads to the killing of the target cell, which is infected by virus, intracytoplasmic bacterium, or are otherwise damaged or dysfunctional. Additionally, some helper T cells will present their antigen to B cells, which will activate their proliferation response.

Antigen presentation : In the upper pathway; foreign protein or antigen (1) is taken up by an antigen-presenting cell (2). The antigen is processed and displayed on a MHC II molecule (3), which interacts with a T helper cell (4). In the lower pathway; whole foreign proteins are bound by membrane antibodies (5) and presented to B lymphocytes (6), which process (7) and present antigen on MHC II (8) to a previously activated T helper cell (10), spurring the production of antigen-specific antibodies (9).

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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.”

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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12.3B: Antigen-Presenting Cells (APCs)

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Describe the overall function of antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B-lymphocytes in terms of the following: how they "process" exogenous antigens how they "process" endogenous antigens the types of MHC molecule to which they attach peptides the role of proteasomes in the binding of peptides from endogenous antigens by MHC-I molecules. the role of lysosomes in the binding of peptides from exogenous antigens by MHC-II molecules. the types of cells to which they present peptides Name the primary type of cell that functions as an antigen-presenting cell to naive T4-lymphocytes and naive T8-lymphocytes. State the role of T4-effector cells in activating macrophages. State the role of T4-effector cells in the proliferation and differentiation of activated B-lymphocytes.

The primary function of dendritic cells, then, is to capture and present protein antigens to naive T-lymphocytes. (Naive lymphocytes are those that have not yet encountered an antigen.) Since dendritic cells are able to express both MHC-I and MHC-II molecules, they are able to present antigens to both naive T8-lymphocytes and naive T4-lymphocytes.

These interactions enable the naiveT4-lymphocyte or T8-lymphocyte to become activated, proliferate, and differentiate into effector lymphocytes. (Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.)

1. MHC-II presentation of protein antigens to naive T4-lymphocytes

a. MHC-II presentation of exogenous antigens to naive T4-lymphocytes

Immature dendritic cells take in protein antigens for attachment to MHC-II molecules and subsequent presentation to naive T4-lymphocytes by:

1. Receptor-mediated phagocytosis, e.g., PAMPs binding to endocytic PRRs, IgG or C3b attachment of microbes to phagocytes during opsonization (see Figure \(\PageIndex{2}\)) .

2. Macropinocytosis, a process where large volumes of surrounding fluid containing microbes are engulfed. This also enables dendritic cells to take in some encapsulated bacteria that might resist classical phagocytosis (see Figure \(\PageIndex{3}\)) .

The binding of microbial PAMPs to the PRRs of the immature dendritic cell activates that dendritic cell and promotes production of the chemokine receptor CCR7 that directs the dendritic cell into local lymphoid tissue. Following maturation, the dendritic cell can now present protein epitopes bound to MHC molecules to all the various naive T-lymphocytes passing through the lymphoid system (See Figure \(\PageIndex{4}\) and Figure \(\PageIndex{5}\) ).

The MHC-II molecules bind peptide epitopes from exogenous antigens and place them on the surface of the dendritic cell (see Figure \(\PageIndex{6}\)) . Here the MHC-II/peptide complexes can be recognized by complementary shaped TCRs and CD4 molecules on naive T4-lymphocytes (see Figure \(\PageIndex{7}\)) .

b. MHC-II cross-presentation of endogenous antigens to naive T4-lymphocytes

While most dendritic cells present exogenous antigens to naive T4-lymphocytes, certain dendritic cells are capable of cross-presentation of endogenous antigens to naive T4-lymphocytes. In this way, T4-lymphocytes can play a role in defending against both exogenous and endogenous antigens. This is done via autophagy, the cellular process whereby the cell's own cytoplasm is taken into specialized vesicles called autophagosomes (See Figure \(\PageIndex{8}\)) . The autophagosomes subsequently fuse with lysosomes containing proteases that will degrade the proteins in the autophagosome into peptides. From here, the peptides are transported into the vesicles containing MHC-II molecules where they can bind to the MHC-II groove, be transported to the surface of the denritic cell, and interact with the TCRs and CD4 molecules of naive T4-lymphocytes (See Figure \(\PageIndex{8}\)) .

2. MHC-I presentation of protein antigens to naive T8-lymphocytes

Immature dendritic cells take in protein antigens for attachment to MHC-I molecules and subsequent presentation to naive T8-lymphocytes.

a. MHC-I presentation of endogenous antigens to naive T8-lymphocytes

During the replication of viruses and intracellular bacteria within their host cell, as well as during the replication of tumor cells, viral, bacterial, or tumor proteins are degraded into a variety of peptide epitopes by cylindrical organelles called proteasomes. The body's own cytosolic proteins are also degraded into peptides by proteasomes.

These peptide epitopes are then attached to a groove of MHC-I molecules that are then transported to the surface of that cell where they can be recognized by a complementary-shaped T-cell receptor (TCR) and a CD8 molecule, a co-receptor, on the surface of either a naive T8-lymphocyte or a cytotoxic T-lymphocyte (CTL). The TCRs recognize both the foreign peptide antigen and the MHC molecule. TCRs, however, will not recognize self-peptides bound to MHC-I. As a result, normal cells are not attacked and killed.

MHC-I molecule with bound peptide on the surface of antigen-presenting dendritic cells ; see Figure \(\PageIndex{9}\) can be recognized by a complementary-shaped TCR/CD8 on the surface of a naive T8-lymphocyte to initiate cell-mediated immunity (see Figure \(\PageIndex{10}\)) .

b. MHC-I cross-presentation of exogenous antigens to naive T8-lymphocytes

While most dendritic cells present endogenous antigens to naive T8-lymphocytes, certain dendritic cells are capable of cross-presentation of exogenous antigens to naive T8-lymphocytes. In this way, T8-lymphocytes can play a role in defending against both exogenous and endogenous antigens. There are two proposed mechanisms for cross-presentation of exogenous antigens to T8-lymphocytes:

1. The dendritic cell engulfs the exogenous antigen and places it in a phagosome which then fuses with a lysosome to form a phagolysosome. The antigen is partially degraded in the phagolysosome where proteins are translocated into the cytoplasm where they are processed into peptides by proteasomes, enter the endoplasmic reticulum, and are bound to MHC-I molecules (see Figure \(\PageIndex{11}\)) .

2. The dendritic cell engulfs the exogenous antigen and places it in a phagosome which then fuses with a lysosome to form a phagolysosome. The protein antigens are degraded into peptides within the phagolysosome which then directly fuses with vesicles containing MHC-I molecules to which the peptides subsequently bind (see Figure \(\PageIndex{12}\)) .

In addition, dendritic cells are very susceptible to infection by many different viruses. Once inside the cell, the viruses become endogenous antigens in the cytosol. Once in the cytosol, the viral proteins from the replicating viruses are degraded into peptides by proteasomes where they subsequently bind to MHC-I molecules.

The binding of microbial PAMPs to the PRRs of the immature dendritic cell activates that dendritic cell and promotes production of the chemokine receptor CCR7 that directs the dendritic cell into local lymphoid tissue. Following maturation, the dendritic cell can now present protein epitopes bound to MHC molecules to all the various naive T-lymphocytes passing through the lymphoid system.

To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #1 see the Web page for the University of Illinois College of Medicine.

To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes, #2 see the Web page for the University of Illinois College of Medicine.

Why is this essential for effective adaptive immunity ?

For a Summary of Key Surface Molecules and Cellular Interactions of Antigen-Presenting Dendritic Cells, see Figure \(\PageIndex{13}\) .

Macrophages

As we learned in Unit 5, when monocytes leave the blood and enter the tissue, they become activated and differentiate into macrophages. Those that have recently left the blood during inflammation and move to the site of infection are sometimes referred to as wandering macrophages. In addition, the body has macrophages already stationed throughout the tissues and organs of the body. These are sometimes referred to as fixed macrophages. Many fixed macrophages are part of the mononuclear phagocytic (reticuloendothelial) system. They, along with B-lymphocytes and T-lymphocytes, are found supported by reticular fibers in lymph nodules, lymph nodes, and the spleen where they filter out and phagocytose foreign matter such as microbes. Similar cells derived from stem cells, monocytes, or macrophages are also found in the liver (Kupffer cells), the kidneys (mesangial cells), the brain (microglia), the bones (osteoclasts), the lungs (alveolar macrophages), and the gastrointestinal tract (peritoneal macrophages).

The primary function of macrophages, then, is to capture and present protein antigens to effector T-lymphocytes. (Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.)

The MHC-II molecules bind peptide epitopes from exogenous antigens and place them on the surface of the macrophages. Here the MHC-II/peptide complexes can be recognized by complementary shaped T-cell receptors (TCRs) and CD4 molecules on an effector T4-lymphocytes ; see Fig.14 .

Effector T4-lymphocytes called T H 1 cells coordinate immunity against intracellular bacteria and promote opsonization by macrophages.

1. They produce cytokines such as interferon-gamma (IFN- ? ) that promote cell-mediated immunity against intracellular pathogens, especially by activating macrophages that have either ingested pathogens or have become infected with intracellular microbes such as Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania donovani , and Pneumocystis jiroveci that are able to grow in the endocytic vesicles of macrophages. Activation of the macrophage by T H 1 cells greatly enhances their antimicrobial effectiveness (see Figure \(\PageIndex{14}\)) .

2. They produce cytokines that promote the production of opsonizing and complement activating IgG that enhances phagocytosis (see Figure \(\PageIndex{15}\)) .

3. They produce receptors that bind to and kill chronically infected cells, releasing the bacteria that were growing within the cell so they can be engulfed and killed by macrophages.

4. They produce cytokines such as tumor necrosis factor-alpha (TNF-a) that promote diapedesis of macrophages.

5. They produce the chemokine CXCL2 to attract macrophages to the infection site.

There is growing evidence that monocytes and macrophages can be “trained” by an earlier infection to do better in future infections, that is, develop memory. It is thought that microbial pathogen-associated molecular patterns (PAMPs) binding to pattern-recognition (PRRs) on monocytes and macrophages triggers the cell’s epigenome to reprogram or train that cell to react better against new infections.

For a Summary of Key Surface Molecules and Cellular Interactions of Antigen-Presenting Macrophages, see Figure \(\PageIndex{16}\) .

B-lymphocytes

Like all lymphocytes, B-lymphocytes circulate back and forth between the blood and the lymphoid system of the body. B-lymphocytes are able to capture and present peptide epitopes from exogenous antigens to effector T4-lymphocytes. The MHC-II molecules bind peptide epitopes from exogenous antigens and place them on the surface of the B-lymphocytes. Here the MHC-II/peptide complexes can be recognized by complementary shaped T-cell receptors (TCRs) and CD4 molecules on an effector T4-lymphocytes (see Figure \(\PageIndex{17}\)) . This interaction eventually triggers the effector T4-lymphocyte to produce and secrete various cytokines that enable that B-lymphocyte to proliferate and differentiate into antibody-secreting plasma cells (see Figure \(\PageIndex{18}\)) .

For a Summary of Key Surface Molecules and Cellular Interactions of Antigen-Presenting B-Lymphocytes, see Figure \(\PageIndex{19}\) .

• Antigen-presenting cells (APCs) include dendritic cells, macrophages, and B-lymphocytes.
• APCs express both MHC-I and MHC-II molecules and serve two major functions during adaptive immunity: they capture and process antigens for presentation to T-lymphocytes, and they produce signals required for the proliferation and differentiation of lymphocytes.
• Most dendritic cells are derived from monocytes and are referred to as myeloid dendritic cells and are located under the surface epithelium of the skin, the mucous membranes of the respiratory tract, genitourinary tract, and the gastrointestinal tract, and throughout the body's lymphoid tissues and in most solid organs.
• The primary function of dendritic cells is to capture and present protein antigens to naive T-lymphocytes which enables the naïve T4-lymphocytes or T8-lymphocytes to become activated, proliferate, and differentiate into effector cells.
• Naïve lymphocytes are B-lymphocytes and T-lymphocytes that have not yet reacted with an epitope of an antigen.
• Dendritic cells use MHC-II molecules to present protein antigens to naïve T4-lymphocytes and MHC-I molecules to present protein antigens to naïve T8-lymphocytes.
• When monocytes leave the blood and enter the tissue, they become activated and differentiate into macrophages.
• When functioning as APCs, macrophages capture and present peptide epitopes from exogenous antigens to effector T4-lymphocytes.
• Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.
• B-lymphocytes mediate antibody production.
• When functioning as APCs, B-lymphocytes are able to capture and present peptide epitopes from exogenous antigens to effector T4-lymphocytes.
• To activate naïve T4-lymphocytes, dendritic cells engulf exogenous antigens, place them in a phagosome, degrade protein antigens into peptides via lysosomes, bind those peptides to MHC-II molecules and transport them to the surface of the dendritic cell where they can be recognized by the T-cell receptors and CD4 molecules of naïve T4-lymphocytes.
• To activate naïve T8-lymphocytes, dendritic cells degrade endogenous protein antigens into peptides via their proteasomes, bind those peptides to MHC-I molecules and transport them to the surface of the dendritic cell where they can be recognized by the T-cell receptors and CD8 molecules of naïve T8-lymphocytes.

Antigen processing and presentation: Cytosolic and Endocytic pathway

August 3, 2020 Gaurab Karki Immunology 0

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.

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.

• Antigen processing and presentationCytosolic and Endocytic pathway

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• Review Article
• Published: 16 June 2023

Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy

• Kailin Yang 1 ,
• Ahmed Halima 1 &
• Timothy A. Chan   ORCID: orcid.org/0000-0002-9265-0283 1 , 2 , 3 , 4  

Nature Reviews Clinical Oncology volume  20 ,  pages 604–623 ( 2023 ) Cite this article

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• Immunotherapy
• Predictive markers
• Tumour immunology

Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour control is only achieved in a fraction of patients who receive these therapies. Understanding the mechanisms underlying clinical response and resistance to treatment is therefore essential to expanding the level of clinical benefit obtained from immunotherapies. In this Review, we describe the molecular mechanisms of antigen processing and presentation in tumours and their clinical consequences. We examine how various aspects of the antigen-presentation machinery (APM) shape tumour immunity. In particular, we discuss genomic variants in HLA alleles and other APM components, highlighting their influence on the immunopeptidomes of both malignant cells and immune cells. Understanding the APM, how it is regulated and how it changes in tumour cells is crucial for determining which patients will respond to immunotherapy and why some patients develop resistance. We focus on recently discovered molecular and genomic alterations that drive the clinical outcomes of patients receiving immune-checkpoint inhibitors. An improved understanding of how these variables mediate tumour–immune interactions is expected to guide the more precise administration of immunotherapies and reveal potentially promising directions for the development of new immunotherapeutic approaches.

The clinical success of immune-checkpoint inhibitors has improved cancer care, although long-term durable remission is only achieved in a subset of patients.

Antigen processing and presentation by tumour cells are essential for long-lasting immune surveillance.

Alterations in the genes encoding MHC components and other parts of the antigen-presentation machinery are frequently found across several cancer types and are associated with both tumour development and the effectiveness of immunotherapies.

MHC-based antigen presentation exerts strong evolutionary pressure on the immunopeptidome, which in turn shapes the mutational landscape of the tumour genome.

Germline human leukocyte antigen diversity and somatic aberrations in the antigen-presentation machinery inform the therapeutic response to immune-checkpoint inhibitors.

Development of novel therapies based on an accurate understanding of antigen presentation in the setting of tumour–immune dynamics is crucial to the development of improved therapeutic approaches.

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Acknowledgements

The authors are grateful for the support from NIH grants R35CA232097 (T.A.C.), R01CA205426 (T.A.C.), U54CA274513 (T.A.C.) and T32CA094186 (K.Y.), a Young Investigator Award from ASCO Conquer Cancer Foundation (K.Y.), a RSNA Research Resident Grant (K.Y.), and a Cleveland Clinic VeloSano Impact Award (K.Y.).

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Kailin Yang, Ahmed Halima & Timothy A. Chan

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Timothy A. Chan

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T.A.C. is a co-founder of and holds equity in Gritstone Oncology; holds equity in An2H; acknowledges grant funding from An2H, AstraZeneca, Bristol Myers Squibb, Eisai, Illumina and Pfizer; has served as an advisor for An2H, AstraZeneca, Bristol Myers Squibb, Eisai, Illumina and MedImmune; and holds ownership of intellectual property on using tumour mutational burden to predict immunotherapy response, which has been licensed to PGDx. K.Y. and A.H. declare no competing interests.

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Yang, K., Halima, A. & Chan, T.A. Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy. Nat Rev Clin Oncol 20 , 604–623 (2023). https://doi.org/10.1038/s41571-023-00789-4

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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

Chapter 5 antigen presentation to t lymphocytes.

In an adaptive immune response , antigen is recognized by two distinct sets of highly variable receptor molecules—the immunoglobulins that serve as antigen receptors on B cells and the antigen-specific receptors of T cells . As we saw in Chapter 3, T cells recognize only antigens that are displayed on cell surfaces. These antigens may derive from pathogens that replicate within cells, such as viruses or intracellular bacteria , or from pathogens or their products that cells internalize by endocytosis from the extracellular fluid. T cells can detect the presence of intracellular pathogens because infected cells display on their surface peptide fragments derived from the pathogens' proteins. These foreign peptides are delivered to the cell surface by specialized host-cell glycoproteins, the MHC molecules , which are also described in Chapter 3. The MHC glycoproteins are encoded in a large cluster of genes that were first identified by their potent effects on the immune response to transplanted tissues. For that reason, the gene complex was termed the major histocompatibility complex (MHC) . We now know that within this region of the genome, in addition to those genes encoding the MHC molecules themselves, are many genes whose products are involved in the production of the MHC:peptide complexes.

We will begin by discussing the mechanisms of antigen processing and presentation, whereby protein antigens are degraded into peptides inside cells and the peptides are then carried to the cell surface bound to MHC molecules . We will see that the two different classes of MHC molecule, known as MHC class I and MHC class II, deliver peptides from different cellular compartments to the surface of the infected cell. Peptides from the cytosol are bound to MHC class I molecules and are recognized by CD8 T cells , whereas peptides generated in vesicles are bound to MHC class II molecules and recognized by CD4 T cells . The two functional subsets of T cells are thereby activated to initiate the destruction of pathogens resident in these two different cellular compartments. Some CD4 T cells activate naive B cells that have internalized specific antigen, and thus also stimulate the production of antibodies to extracellular pathogens and their products.

In the second part of this chapter we will see that there are several genes for each class of MHC molecule: that is, the MHC is polygenic . Each of these genes has many variants: that is, the MHC is also highly polymorphic. Indeed, the most remarkable feature of the MHC class I and II genes is their genetic variability . MHC polymorphism has a profound effect on antigen recognition by T cells , and the combination of polygeny and polymorphism greatly extends the range of peptides that can be presented to T cells by each individual and each population at risk from an infectious pathogen.

• The generation of T-cell receptor ligands
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• Cite this Page Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Chapter 5, Antigen Presentation to T Lymphocytes.
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