Antigen processing

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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. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens (e.g. viruses), or from phagocytosed pathogens (e.g. bacteria); subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically (considering cross-presentation) involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway (e.g. proteolysis of antigens for binding to MHC I molecules).

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While the joint distinction between the two pathways is useful, there are instances where extracellular-derived peptides are presented in the context of MHC class I and cytosolic peptides are presented in the context of MHC class II (this often happens in dendritic cells).

The endogenous pathway

The endogenous pathway is used to present cellular peptide fragments on the cell surface on MHC class I molecules. If a virus had infected the cell, viral peptides would also be presented, allowing the immune system to recognize and kill the infected cell. Worn out proteins within the cell become ubiquitinated, marking them for proteasome degradation. Proteasomes break the protein up into peptides that include some around nine amino acids long (suitable for fitting within the peptide binding cleft of MHC class I molecules). Transporter associated with antigen processing (TAP), a protein that spans the membrane of the rough endoplasmic reticulum, transports the peptides into the lumen of the rough endoplasmic reticulum (ER). Also within the rough ER, a series of chaperone proteins, including calnexin, calreticulin, ERp57, and Binding immunoglobulin protein (BiP) facilitates the proper folding of class I MHC and its association with β2 microglobulin. The partially folded MHC class I molecule then interacts with TAP via tapasin (the complete complex also contains calreticulin and Erp57 and, in mice, calnexin). Once the peptide is transported into the ER lumen it binds to the cleft of the awaiting MHC class I molecule, stabilizing the MHC and allowing it to be transported to the cell surface by the golgi apparatus.

The exogenous pathway

The exogenous pathway is utilized by specialized antigen-presenting cells to present peptides derived from proteins that the cell has endocytosed. The peptides are presented on MHC class II molecules. Proteins are endocytosed and degraded by acid-dependent proteases in endosomes; this process takes about an hour. [1]

The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by Ii (the invariant chain; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II's export from the ER in a vesicle. This fuses with a late endosome containing the endocytosed, degraded proteins. The invariant chain is then broken down in stages, leaving only a small fragment called "Class II-associated invariant chain peptide" (CLIP) which still blocks the peptide binding cleft. An MHC class II-like structure, HLA-DM, removes CLIP and replaces it with a peptide from the endosome. The stable MHC class-II is then presented on the cell surface. [2]

Cross-presentation processing

In Cross-presentation, peptides derived from extracellular proteins are presented in the context of MHC class I. The cell starts off with the exogenous pathways but diverts the antigens (cytosolic diversion) to the endogenous pathway. This can allow the cell to skip the parts of the endogenous pathway that involve synthesis of antigens from the antigenic genes with cellular machinery upon infection, because the endogenous pathway can involve infection before being able to present antigens with MHC I, and cross-presentation saves them the effort needed for that and allows the professional antigen-presenting cells (dendritic cells) to process and present antigens without getting infected, which does not tend to happen to dendritic cells and is quite common scenario of antigen-processing using the endogenous pathway. [3] Not all antigen-presenting cells utilize cross-presentation.

Viral evasion of antigen processing

Certain species in the Cytolomegavirus family can cause the infected cell to produce proteins like US2, 3, 6, and/or 11. US11 and US2 mislead MHC I to the cytoplasm; US3 inhibits the transportation of MHC I in the ER (a part of the endogenous pathway and cross-presentation); US6 blocks peptide transportation by TAP to MHC I.

Mycobacterium tuberculosis inhibits phagosome-endosome fusion, thus avoiding being destroyed by the harsh environment of the phagosome. [4]

ICP47 from some herpesvirus block transport of the peptide by TAP. U21 from some human herpesvirus 7 binds and targets certain MHC I molecules for lysosomal degradation.

E19 from some adenoviruses block the movement of MHC I to the proper locations for the endogenous pathway.

Nef from some HIV strains enhance the movement of MHC molecules back into the cytoplasm, preventing them from presenting antigens.

The role of Langerhans' dendritic cells in antigen processing

Langerhans' cells are particular type of dendritic cells present in non lymphoid tissues together with interstitial cells. When these cells (in an immature state) come in contact with antigenic cells or disease causing viruses etc. these cells produce an inflammatory stimulus and start antigen processing and move toward lymph nodes where these APCs present antigen to mature T lymphocytes.

T-dependent antigen – Antigens that require the assistance of T cells to induce the formation of specific antibodies. T-independent antigen – Antigens that stimulate B cells directly.

B-cell activation with B-T cell interactions

Lymphocytes are one of the five kinds of white blood cells or leukocytes, circulating in the blood. Although mature lymphocytes all look pretty much alike, they are diverse in their functions. The most abundant lymphocytes are:

B cells are produced in the bone marrow. The precursors of T cells are also produced in the bone marrow but leave the bone marrow and mature in the thymus (which accounts for their designation). Each B cell and T cell is specific for a particular antigen, which simply means that each of these cells is able to bind to a particular molecular structure (such as an antigen). The specificity of binding resides in a specific receptor for antigen: the B-cell receptor (BCR) and the T-cell receptor (TCR) for B and T cells, respectively. Both BCRs and TCRs share these properties:

How antigen receptor diversity is generated

Each receptor has a unique binding site. This site binds to a portion of the antigen called an antigenic determinant or epitope. The binding, like that between an enzyme and its substrate, depends on complementarity of the surface of the receptor and the surface of the epitope and occurs mainly by non-covalent forces. Successful binding of the antigen receptor to the epitope, if accompanied by additional signals, results in:

  1. Stimulation of the cell to leave G0 and enter the cell cycle.
  2. Repeated mitosis leads to the development of a clone of cells bearing the same antigen receptor; that is, a clone of cells of the identical specificity. BCRs and TCRs differ in:

B cells

BCRs bind intact antigens (like diphtheria toxoid, the protein introduced in the diphtheria-tetanus-pertussis vaccine). These may be soluble molecules present in the extracellular fluid; or intact molecules that the B cell plucks from the surface of antigen-presenting cells like macrophages and dendritic cells. The bound antigen molecules are engulfed into the B cell by receptor-mediated endocytosis. The antigen is digested into peptide fragments by various proteasomes and is then displayed at the cell surface attached along with a class II histocompatibility molecule. Helper T cells specific for this structure (i.e., with complementary TCRs) bind this B cell and secrete lymphokines that:

  1. Stimulate the B cell to enter the cell cycle
  2. The B cell undergoes repeated mitotic cell division, resulting in a clone of cells with identical BCRs;
  3. The B cells switch from synthesizing their BCRs as integral membrane proteins to a soluble version;
  4. The clonal cells differentiate into plasma cells that secrete these soluble BCRs, which we now call antibodies

T cells

There are two types of T cells that differ in their TCR:

  1. alpha/beta (αβ) T cells: Their TCR is a heterodimer of an alpha chain with a beta chain. Each chain has a variable (V) region and a constant (C) region. The V regions each contain 3 hypervariable regions that make up the antigen-binding site.
  2. gamma/delta (γδ) T cells: Their TCR is also a heterodimer of a gamma chain paired with a delta chain. They show characteristics of both innate immune response and acquired immune response; hence, regarded as the bridging between the two immune systems.

The discussion that follows now concerns alpha/beta T cells. The TCR (of αβ T-cells) binds a bimolecular complex displayed at the surface of some other cells called an antigen-presenting cell (APC). This complex consists of: a fragment of an antigen lying within the groove of a histocompatibility molecule. The complex has been compared to a "hot dog in a bun".[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is any molecule, molecular structure, foreign particulate matter, or pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. Antigens can be proteins, peptides, polysaccharides, lipids, or nucleic acids.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

<span class="mw-page-title-main">MHC class I</span> Protein of the immune system

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

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, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

<span class="mw-page-title-main">CLIP (protein)</span>

CLIP or Class II-associated invariant chain peptide is the part of the invariant chain (Ii) that binds to the peptide binding groove of MHC class II and remains there until the MHC receptor is fully assembled. CLIP is one of the most prevalent self peptides found in the thymic cortex of most antigen-presenting cells. The purpose of CLIP is to prevent the degradation of MHC II dimers before antigenic peptides bind, and to prevent autoimmunity.

<span class="mw-page-title-main">Polyclonal B cell response</span> Immune response by adaptive immune system

Polyclonal B cell response is a natural mode of immune response exhibited by the adaptive immune system of mammals. It ensures that a single antigen is recognized and attacked through its overlapping parts, called epitopes, by multiple clones of B cell.

A tetramer assay is a procedure that uses tetrameric proteins to detect and quantify T cells that are specific for a given antigen within a blood sample. The tetramers used in the assay are made up of four major histocompatibility complex (MHC) molecules, which are found on the surface of most cells in the body. MHC molecules present peptides to T-cells as a way to communicate the presence of viruses, bacteria, cancerous mutations, or other antigens in a cell. If a T-cell's receptor matches the peptide being presented by an MHC molecule, an immune response is triggered. Thus, MHC tetramers that are bioengineered to present a specific peptide can be used to find T-cells with receptors that match that peptide. The tetramers are labeled with a fluorophore, allowing tetramer-bound T-cells to be analyzed with flow cytometry. Quantification and sorting of T-cells by flow cytometry enables researchers to investigate immune response to viral infection and vaccine administration as well as functionality of antigen-specific T-cells. Generally, if a person's immune system has encountered a pathogen, the individual will possess T cells with specificity toward some peptide on that pathogen. Hence, if a tetramer stain specific for a pathogenic peptide results in a positive signal, this may indicate that the person's immune system has encountered and built a response to that pathogen.

<span class="mw-page-title-main">HLA-DM</span>

HLA-DM is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system. It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins. HLA-DM is encoded by the genes HLA-DMA and HLA-DMB.

<span class="mw-page-title-main">CD74</span> Mammalian protein found in Homo sapiens

HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74, is a protein that in humans is encoded by the CD74 gene. The invariant chain is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses. The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced. That is, despite multiple allelic variations of MHC molecules and multiple peptides presented on antigen presenting cells, the immune response is skewed to only specific combinations of the two. Immunodominance is evident for both antibody-mediated immunity and cell-mediated immunity. Epitopes that are not targeted or targeted to a lower degree during an immune response are known as subdominant epitopes. The impact of immunodominance is immunodomination, where immunodominant epitopes will curtail immune responses against non-dominant epitopes. Antigen-presenting cells such as dendritic cells, can have up to six different types of MHC molecules for antigen presentation. There is a potential for generation of hundreds to thousands of different peptides from the proteins of pathogens. Yet, the effector cell population that is reactive against the pathogen is dominated by cells that recognize only a certain class of MHC bound to only certain pathogen-derived peptides presented by that MHC class. Antigens from a particular pathogen can be of variable immunogenicity, with the antigen that stimulates the strongest response being the immunodominant one. The different levels of immunogenicity amongst antigens forms what is known as dominance hierarchy.

References

  1. ↑ Lee, Tim; McGibbon, Angela. "Dalhousie Immunology Bookcase: T and B cell interaction". Immunology for Medical Students. Dalhousie University. Archived from the original on 4 June 2008. Retrieved 2008-06-23.
  2. ↑ Nesmiyanov, Pavel P. (2020), "Antigen Presentation and Major Histocompatibility Complex", Reference Module in Biomedical Sciences, Elsevier, pp. 90–98, doi:10.1016/b978-0-12-818731-9.00029-x, ISBN   978-0-12-801238-3, S2CID   234948691 , retrieved 2021-12-02
  3. ↑ William R. Heath & Francis R. Carbone (November 2001). "Cross-presentation in viral immunity and self-tolerance". Nature Reviews Immunology. 1 (2): 126–134. doi:10.1038/35100512. PMID   11905820. S2CID   5666741.
  4. ↑ Deretic, V., & Fratti, R. A. (1999). Mycobacterium tuberculosis phagosome. Molecular microbiology, 31(6), 1603-1609. Chicago
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