Lesson 5.1 Study Notes on Major Histocompatibility Complex (MHC)

Introduction to Major Histocompatibility Complex (MHC)

Learning Objectives

  • On completion of this session, you should be able to:

    • Understand the structure and function of MHC molecules.

    • Comprehend the genetics of MHC and the concept of MHC restriction in T cell activation.

MHC and Immunity

  • The relationship between MHC and immunity involves:

    1. Antibodies can recognize antigen alone.

    2. T-cell receptors can only recognize antigen that has been processed and presented by Major Histocompatibility Complex (MHC).

    3. This process involves antigen processing and antigen presentation.

Overview of MHC

  1. The MHC is a complex of genes located on:

    • Short arm of chromosome 6 in humans.

    • Chromosome 17 in mice.

  2. The MHC extends over approximately 4-7 million base pairs (bp).

  3. The MHC comprises more than 200 genes, which are divided into four regions:

    • Class I

    • Class Ib

    • Class II

    • Class III

  4. The products of MHC genes mediate various immune functions:

    1. T cell development.

    2. T cell recognition of antigens.

    3. Rejection of tissue grafts.

    4. Susceptibility to certain disorders.

Chromosome 6: HLA Region Mapping

  • The HLA region on chromosome 6 is key for understanding MHC diversity and functionality:

    • Gene map identifiers:

    • Class II: DP, DQ, DR

    • Class III: C4, C2, Hsp70, TNF

    • Class I: Bf

    • Specific coordinates for HLA region: 6p21.1-21.3.

Class I MHC Genes

  1. Mediates immune responses against endogenous antigens (antigens already found in cells).

  2. Typically found on cells infected with viruses or transformed into tumor cells.

  3. MHC Class I presents peptides that are 8-10 amino acids in size, which cytotoxic T cells recognize.

  4. Found in all nucleated cells.

Class II MHC Genes

  1. Mediates immune response against exogenous antigens (antigens found outside of cells, in the cytosol).

  2. Binds to peptide fragments that are 13-18 amino acids in size, recognized by T helper cells.

  3. MHC Class II proteins are located on:

    • B lymphocytes

    • Macrophages

    • Monocytes

    • Dendritic cells

    • Endothelial cells

  4. These cells are phagocytic and can engulf extracellular antigens.

MHC Haplotypes

  1. A haplotype is defined as a set of genes located on a single chromosome and their associated characteristics.

  2. An individual has two haplotypes for each set of genes (one from mother and one from father).

  3. MHC genes are expressed codominantly, meaning that both maternal and paternal products are expressed in the same cells.

Class I MHC Proteins

  1. Comprise two polypeptide chains:

    • An alpha chain (transmembrane) encoded by MHC.

    • A beta-2 microglobulin chain (encoded by a highly conserved gene on a separate chromosome).

  2. The folded molecule has four domains:

    • a1, a2 (create peptide binding cleft)

    • a3

    • beta-2 microglobulin

Class II MHC Proteins

  1. Comprise two polypeptide chains:

    • An alpha chain.

    • A beta chain.

  2. The folded molecule has four domains:

    • a1, a2, b1, b2 (with b2 being transmembrane).

  3. The a1 and b1 domains comprise the peptide binding cleft.

MHC Protein Structure

  1. Peptide Binding Cleft:

    • The cleft is similarly organized in Class I and Class II proteins.

    • The floor of the cleft is comprised of beta sheets, while the walls are composed of alpha helices.

    • Class I binding clefts are closed, while Class II are open.

    • Peptides lie within the cleft in an extended conformation.

MHC Peptide Binding to Class I

  1. Peptide binding to Class I MHC is selective and exhibits high affinity to only certain peptides.

  2. Peptides are typically 8-9 residues long.

  3. Aliphatic or aromatic residues act as anchor residues that immobilize the peptide within the cleft.

  4. These anchor residues are present in all peptides binding a given MHC class I molecule.

MHC Peptide Binding to Class II

  1. MHC Class II molecules bind peptides that vary in length from 12 to about 17 linear amino acids.

  2. They utilize three (or sometimes four) anchor residues in the central region of the peptide.

  3. The binding characteristics are more diverse, allowing Class II proteins to bind a greater range of peptides, making the prediction of anchor residues more complex.

Self MHC Restriction

  1. T cells can only recognize and respond to antigenic peptides when combined with MHC molecules.

  2. Helper T cells specifically recognize antigens in the context of Class II self MHC.

  3. Cytotoxic T cells recognize antigens in the context of Class I self MHC.

Self MHC Restriction in Cytotoxic T Cells

  • Cytotoxic T cells exclusively kill syngeneic (genetically identical) virally infected target cells.

  • Both the T cell and the infected cell must share the same set of MHC genes for effective immune action.

Summary of MHC Functions and Importance

  1. Understanding the structure and function of MHC molecules is fundamental to immunology.

  2. MHC Class I molecules consist of a heavy alpha chain and a beta-2 microglobulin chain, featuring a peptide-binding groove essential for presenting endogenous antigens to CD8+ cytotoxic T cells.

  3. MHC Class II molecules, composed of alpha and beta chains, present exogenous antigens to CD4+ helper T cells, which are crucial for coordinating immune responses.

  4. MHC restriction is the principle that T cells can only recognize antigens presented by the body's own MHC molecules. This mechanism ensures that T cells respond specifically to cells displaying foreign antigens in the context of self-MHC, thereby maintaining immune precision and preventing inappropriate immune activation.