MHC restriction

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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. [1]

Contents

When foreign proteins enter a cell, they are broken into smaller pieces called peptides. These peptides, also known as antigens, can derive from pathogens such as viruses or intracellular bacteria. Foreign peptides are brought to the surface of the cell and presented to T cells by proteins called the major histocompatibility complex (MHC). During T cell development, T cells go through a selection process in the thymus to ensure that the T cell receptor (TCR) will not recognize MHC molecule presenting self-antigens, i.e that its affinity is not too high. High affinity means it will be autoreactive, but no affinity means it will not bind strongly enough to the MHC. The selection process results in developed T cells with specific TCRs that might only respond to certain MHC molecules but not others. The fact that the TCR will recognize only some MHC molecules but not others contributes to "MHC restriction". The biological reason of MHC restriction is to prevent supernumerary wandering lymphocytes generation, hence energy saving and economy of cell-building materials. [2]

T-cells are a type of lymphocyte that is significant in the immune system to activate other immune cells. T-cells will recognize foreign peptides through T-cell receptors (TCRs) on the surface of the T cells, and then perform different roles depending on the type of T cell they are in order to defend the host from the foreign peptide, which may have come from pathogens like bacteria, viruses or parasites. Enforcing the restriction that T cells are activated by peptide antigens only when the antigens are bound to self-MHC molecules, MHC restriction adds another dimension to the specificity of T cell receptors so that an antigen is recognized only as peptide-MHC complexes. [3]

MHC restriction in T cells occurs during their development in the thymus, specifically positive selection. [4] Only the thymocytes (developing T cells in the thymus) that are capable of binding, with an appropriate affinity, with the MHC molecules can receive a survival signal and go on to the next level of selection. MHC restriction is significant for T cells to function properly when it leaves the thymus because it allows T cell receptors to bind to MHC and detect cells that are infected by intracellular pathogens, viral proteins and bearing genetic defects. Two models explaining how restriction arose are the germline model and the selection model.

The germline model suggests that MHC restriction is a result of evolutionary pressure favoring T cell receptors that are capable of binding to MHC. [5] The selection model suggests that not all T cell receptors show MHC restriction, however only the T cell receptors with MHC restriction are expressed after thymus selection. [6] In fact, both hypotheses are reflected in the determination of TCR restriction, such that both germline-encoded interactions between TCR and MHC and co-receptor interactions with CD4 or CD8 to signal T cell maturation occur during selection. [7]

Introduction

The TCRs of T cells recognize linear peptide antigens only if coupled with a MHC molecule. In other words, the ligands of TCRs are specific peptide-MHC complexes. [8] MHC restriction is particularly important for self-tolerance, which makes sure that the immune system does not target self-antigens. When primary lymphocytes are developing and differentiating in the thymus or bone marrow, T cells die by apoptosis if they express high affinity for self-antigens presented by an MHC molecule or express too low an affinity for self MHC. [9]

T cell maturation involves two distinct developmental stages: positive selection and negative selection. Positive selection ensures that any T-cells with a high enough affinity for MHC bound peptide survive and goes on to negative selection, while negative selection induces death in T-cells which bind self-peptide-MHC complex too strongly. Ultimately, the T-cells differentiate and mature to become either T helper cells or T cytotoxic cells. At this point the T cells leave the primary lymphoid organ and enter the blood stream. [10]

The interaction between TCRs and peptide-MHC complex is significant in maintaining the immune system against foreign antigens. MHC restriction allows TCRs to detect host cells that are infected by pathogens, contains non-self proteins or bears foreign DNA. However, MHC restriction is also responsible for chronic autoimmune diseases and hypersensitivity. [8]

Structural specificity

HLA-A projected away from the cell surface and presenting a peptide sequence. Illustration HLA-A.png
HLA-A projected away from the cell surface and presenting a peptide sequence.

The peptide-MHC complex presents a surface that looks like an altered self to the TCR. [11] The surface consisting of two α helices from the MHC and a bound peptide sequence is projected away from the host cell to the T cells, whose TCRs are projected away from the T cells towards the host cells. In contrast with T cell receptors which recognize linear peptide epitopes, B cell receptors recognize a variety of conformational epitopes (including peptide, carbohydrate, lipid and DNA) with specific three-dimensional structures. [8]

Imposition

The imposition of MHC restriction on the highly variable TCR has caused heated debate. Two models have been proposed to explain the imposition of MHC restriction. The Germline model proposes that MHC restriction is hard-wired in the TCR Germline sequence due to co-evolution of TCR and MHC to interact with each other. The Selection model suggests that MHC restriction is not a hard-wired property in the Germline sequences of TCRs, but imposed on them by CD4 and CD8 co-receptors during positive selection. The relative importance of the two models are not yet determined. [12]

Germline model

The Germline hypothesis suggests that the ability to bind to MHC is intrinsic and encoded within the germline DNA that are coding for TCRs. This is because of evolutionary pressure selects for TCRs that are capable of binding to MHC and selects against those that are not capable of binding to MHC. [13] Since the emergence of TCR and MHC ~500 million years ago, [14] there is ample opportunity for TCR and MHC to coevolve to recognize each other. Therefore, it is proposed that evolutionary pressure would lead to conserved amino acid sequences at regions of contact with MHCs on TCRs. [12]

Evidence from X-ray crystallography has shown comparable binding topologies between various TCR and MHC-peptide complexes. [15] In addition, conserved interactions between TCR and specific MHCs support the hypothesis that MHC restriction is related to the co-evolution of TCR and MHC to some extent. [16]

Selection model

The selection hypothesis argues that instead of being an intrinsic property, MHC restriction is imposed on the T cells during positive thymic selection after random TCRs are produced. [17] According to this model, T cells are capable of recognizing a variety of peptide epitopes independent of MHC molecules before undergoing thymic selection. During thymic selection, only the T cells with affinity to MHC are signaled to survive after the CD4 or CD8 co-receptors also bind to the MHC molecule. This is called positive selection. [18]

Interaction of TCR and co-receptors CD4 and CD8 with MHC molecules. 063-T-CellReceptor-MHC.tiff
Interaction of TCR and co-receptors CD4 and CD8 with MHC molecules.

During positive selection, co-receptors CD4 and CD8 initiate a signaling cascade following MHC binding. [19] This involves the recruitment of Lck, a tyrosine kinase essential for T cell maturation that is associated with the cytoplasmic tail of the CD4 or CD8 co-receptors. Selection model argues that Lck is directed to TCRs by co-receptors CD4 and CD8 when they recognize MHC molecules. [4] Since TCRs interact better with Lck when they are binding to the MHC molecules that are binding to the co-receptors in a ternary complex, T cells that can interact with MHCs bound to by the co-receptors can activate the Lck kinase and receive a survival signal. [12]

Supporting this argument, genetically modified T cells without CD4 and CD8 co-receptors express MHC-independent TCRs. [18] It follows that MHC restriction is imposed by CD4 and CD8 co-receptors during positive selection of T cell selection.

Reconciliation

A reconciliation of the two models was offered later on [7] suggesting that both co-receptor and germline predisposition to MHC binding play significant roles in imposing MHC restriction. Since only those T cells that are capable of binding to MHCs are selected for during positive selection in the thymus, to some extent evolutionary pressure selects for germline TCR sequences that bind MHC molecules. On the other hand, as suggested by the selection model, T cell maturation requires the TCRs to bind to the same MHC molecules as the CD4 or CD8 co-receptor during T cell selection, thus imposing MHC restriction. [12]

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 a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<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">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<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.

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, or from phagocytosed pathogens ; 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 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.

<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.

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A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

<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.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

Human leukocyte histocompatibility complex DO (HLA-DO) is an intracellular, dimeric non-classical Major Histocompatibility Complex (MHC) class II protein composed of α- and β-subunits which interact with HLA-DM in order to fine tune immunodominant epitope selection. As a non-classical MHC class II molecule, HLA-DO is a non-polymorphic accessory protein that aids in antigenic peptide chaperoning and loading, as opposed to its classical counterparts, which are polymorphic and involved in antigen presentation. Though more remains to be elucidated about the function of HLA-DO, its unique distribution in the mammalian body—namely, the exclusive expression of HLA-DO in B cells, thymic medullary epithelial cells, and dendritic cells—indicate that it may be of physiological importance and has inspired further research. Although HLA-DM can be found without HLA-DO, HLA-DO is only found in complex with HLA-DM and exhibits instability in the absence of HLA-DM. The evolutionary conservation of both DM and DO, further denote its biological significance and potential to confer evolutionary benefits to its host.

In immunology, clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

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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.

<span class="mw-page-title-main">K. Christopher Garcia</span>


K. Christopher "Chris" Garcia, Ph.D., is an American scientist known for his research on the molecular and structural biology of cell surface receptors. Garcia is a professor in the Departments of Molecular and Cellular Physiology and Structural Biology at the Stanford University School of Medicine, an Investigator of the Howard Hughes Medical Institute and a member of the National Academies of Science and Medicine. In addition to his role at Stanford, Garcia is a co-founder of several biotechnology companies, including Alexo Therapeutics, Surrozen, and 3T Biosciences.

<span class="mw-page-title-main">Cortical thymic epithelial cells</span>

Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.

References

  1. ↑ Immunobiology: The Immune System in Health and Disease. 5th edition. Janeway CA Jr, Travers P, Walport M, et al. New York: Garland Science; 2001. https://www.ncbi.nlm.nih.gov/books/NBK10757/
  2. ↑ Nesmiyanov, P (2020). "Antigen Presentation and Major Histocompatibility Complex". Reference Module in Biomedical Sciences: 90–98. doi:10.1016/B978-0-12-818731-9.00029-X. ISBN   9780128012383. S2CID   234948691.
  3. ↑ Charles A Janeway, Jr; Travers, Paul; Walport, Mark; Shlomchik, Mark J. (2001-01-01). "Antigen Recognition by B-cell and T-cell Receptors". Garland Science.{{cite journal}}: Cite journal requires |journal= (help)
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  19. ↑ Merwe, P. Anton van der; Cordoba, Shaun-Paul (2011-01-28). "Late Arrival: Recruiting Coreceptors to the T Cell Receptor Complex". Immunity. 34 (1): 1–3. doi: 10.1016/j.immuni.2011.01.001 . ISSN   1074-7613. PMID   21272780.
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