Genetics and classification of MHC genes
The genetic space of MHC spans about 4 million base pairs and contains over 200 genes. In humans, this complex is called HLA (Human leukocyte antigens), and in mice, where it was discovered, it is called H-2. There are three main classes of genes in the complex:
- MHC class I: include highly polymorphic classical genes (HLA-A, B, C), which are involved in antigen presentation, and non-classical genes with limited polymorphism (HLA-E, F, G, H).
- MHC class II: comprise the DP, DQ, and DR loci, whose products present antigens predominantly for cellular immunity. This also includes non-classical genes that ensure intracellular processing (TAP, LMP, HLA-DM).
- MHC class III: encode complement system components (C4, C2), tumor necrosis factors (TNF), and heat shock proteins. They do not encode histocompatibility molecules and do not participate in antigen presentation.
Structure of MHC class I and II molecules
Class I and II gene products are polymorphic membrane proteins. Their membrane-proximal domains belong to the immunoglobulin superfamily, while the distal domains form a specialized antigen-binding cleft (groove).
- MHC class I molecule: consists of a heavy $\alpha$-chain (45 kDa) that spans the membrane and has three extracellular domains ($\alpha_1, \alpha_2, \alpha_3$). A light chain—$\beta_2$-microglobulin (12 kDa)—is non-covalently attached to it. The light chain lacks a transmembrane segment and is encoded outside the MHC complex (on chromosome 15).
- MHC class II molecule: a symmetrical structure consisting of an $\alpha$-chain (33–35 kDa) and a $\beta$-chain (29 kDa). Both chains span the membrane and possess two extracellular domains each. The polymorphism of MHC-II molecules is primarily driven by the variability of the $\beta$-chain.
Features of the antigen-binding cleft
The peptide-binding groove is located at the top of the molecule. Its floor is lined with a $\beta$-pleated sheet structure, and its walls are formed by $\alpha$-helices. This is precisely where the antigen fragment binds, forming a ligand recognized by the T-cell receptor (TCR).
- In MHC I the cleft is closed at both ends. It is formed entirely by the $\alpha_1$ and $\alpha_2$ domains of a single heavy chain. Its capacity is strictly limited: it accommodates peptides 8–10 amino acid residues in length.
- In MHC II the cleft is open at the sides. It is formed by two different chains ($\alpha_1$ and $\beta_1$ domains). Due to the open ends, the size of the bound peptides varies from 12 to 25 amino acid residues (the ends of a long peptide may protrude beyond the cleft).
Tissue distribution and CD1 molecules
Cellular expression of these molecules is strictly regulated:
- MHC-I are present on virtually all nucleated cells (approximately 7,000 molecules per cell). They are absent on erythrocytes and syncytiotrophoblast cells.
- MHC-II have a restricted distribution. Normally, they are expressed only on antigen-presenting cells (APCs): dendritic cells, B lymphocytes, and activated macrophages. Interferon-gamma ($IFN\gamma$) serves as the classical inducer of their appearance.
CD1 molecules, encoded on chromosome 1, are considered separately. Structurally, they resemble MHC-I (possessing an $\alpha$-chain and $\beta_2$-microglobulin), but their closed antigen-binding cleft is designed to bind lipids and lipopeptides (including bacterial mycolic acid), which they present to T cells.
Briefly: answers to topical questions
Which T-lymphocyte subpopulations do MHC class I and class II molecules present antigens to?
MHC class I and class II molecules present antigens to two major subpopulations of $\alpha\beta$ T lymphocytes that differ in their coreceptor expression.
- CD8+ T lymphocytes (CTLs, cytotoxic T lymphocytes)—recognize antigenic peptides strictly in the context of MHC class I molecules.
- CD4+ T lymphocytes (T helper cells)—recognize antigenic peptides exclusively in the context of MHC class II molecules.
The restriction rule is due to the fact that the CD4 coreceptor specifically binds to MHC-II, while the CD8 coreceptor has a high affinity for MHC-I.
What is the specific function of TAP and LMP proteins in antigen processing?
TAP and LMP proteins provide intracellular processing of endogenous antigens for their subsequent loading into MHC class I molecules.
- LMP proteins (LMP2, LMP-7)—encode components of immunoproteasomes, which cleave intracellular proteins into peptides with basic and hydrophobic C-termini.
- TAP proteins (TAP1, TAP2)—encode components of the transport system that move generated antigenic peptides from the cytosol into the endoplasmic reticulum for loading onto MHC-I molecules.
How does the processing of exogenous antigens for presentation by MHC II molecules occur?
The processing of exogenous antigens for presentation by MHC class II molecules involves several consecutive stages within the antigen-presenting cell.
- Endocytosis and cleavage—exogenous proteins are engulfed by the cell and cleaved into peptides in early and late endosomes.
- Synthesis and transport—MHC-II $\alpha$ and $\beta$ chains are synthesized in the endoplasmic reticulum together with the invariant chain and transported to MIIC granules.
- Fusion and loading—MIIC granules fuse with late endosomes, where the invariant chain remnant (CLIP) is replaced by an exogenous peptide with the participation of the HLA-DM molecule.
- Exocytosis—the vesicle fuses with the cell membrane to display the complex.
Which cytokines stimulate the expression of MHC class I molecules on cells?
The expression of MHC class I molecules on the cell surface is stimulated by interferon-gamma.
- Interferon-gamma (IFN$\gamma$)—enhances the expression of MHC-I molecules on the surface of antigen-presenting cells (macrophages and dendritic cells).
The density of MHC-I expression on nucleated cells averages about 7,000 molecules, but it is not constant and can change under the influence of cytokines. IFN$\gamma$ also induces immunoproteasome formation, stimulating antigen processing for efficient presentation.
The class number indicates the structure of the cleft: MHC I = 1 polypeptide chain forms the cleft (closed, short peptides of 8–10 aa). MHC II = 2 different chains form the cleft (open, long peptides of 12–25 aa).
Class and exam questions
What is the difference between antigen recognition by T cells and B cells?
B-cell receptors (BCRs) and antibodies can recognize epitopes within any protein molecules. The T-cell receptor (TCR) recognizes peptides strictly in a complex with MHC molecules on the surface of antigen-presenting cells ("altered self").
Why does graft rejection occur during tissue transplantation?
MHC genes exhibit unprecedentedly high population polymorphism. Due to allelic differences, transplanted cells carry foreign variants of MHC molecules, which the recipient's immune system recognizes as alloantigens and destroys.
How many variants of MHC molecules can exist in a single organism?
Despite thousands of alleles in the population, any single individual's cells carry no more than 16 variants of MHC molecules (products of allelic genes from both parents).
What else to study on this topic
- Mechanisms of intracellular antigen processing
- The role of TAP and LMP genes in peptide preparation
- Binding specificity: the role of "anchor" amino acid residues
- Functions of non-classical MHC genes (HLA-E, F, G, H)
- CD1d molecules and presentation of autologous glycolipids
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