Introduction to Major Histocompatibility Complex (MHC) PDF

Introduction to Major Histocompatibility Complex (MHC) Learning Objectives On completion of this session you should be able to 1) Understand the structure and function of MHC molecules. 2) Comprehend the genetics of MHC and the concept of MHC restriction in T cell activation. How is...

Introduction to Major Histocompatibility Complex (MHC) Learning Objectives On completion of this session you should be able to 1) Understand the structure and function of MHC molecules. 2) Comprehend the genetics of MHC and the concept of MHC restriction in T cell activation. How is MHC related to immunity? 1) Antibodies can recognise antigen alone 2) T-cell receptors can only recognise antigen that has been processed and presented by Major Histocompatibility Complex (MHC) 3) Involves antigen processing and antigen presentation MHC 1) The MHC is a complex of genes located on the short arm of chromosome 6 in humans and chromosome 17 in mice 2) The MHC extends over 4-7 x 106 bp 3) The MHC comprises more than 200 genes divided into 4 regions designated as Class I, Class Ib, II and III 4) The products of the MHC genes mediate: 1. T cell development 2. T cell recognition of antigen 3. Rejection of tissue grafts 4. Susceptibility to certain disorders MHC 1) The most important products are the Class I and Class II proteins 2) The function of these proteins is to present peptide fragments to T cells 3) The MHC protein with bound peptide is the TCR ligand 4) CD8+ T cells bind to MHC Class I:peptide complexes 5) CD4+ T cells bind MHC Class II:peptide complexes Class I MHC Genes 1) Mediates immune responses against endogenous antigens, antigens that are already found in cells 2) Usually these cells that are expressing MHC class 1 are viral- infected or are tumour cells 3) MHC Class I presents peptides that are 8-10 amino acids in size, which will then be recognised by the cytotoxic T cells 4) Found in all nucleated cells Class II MHC Genes 1) Mediate immune response against exogenous antigens, antigens that are found outside of the cells, in the cytosol 2) Bind with amino acid residues that are 13-18 in size and will be recognised by T helper cells 3) MHC class II protein is found on cells like B lymphocytes, macrophages, monocytes, dendritic cells and endothelial cells 4) These cells are phagocytic and can engulf an extracellular antigen MHC Haplotypes 1) Set of genes located on a single chromosome and the characteristic dependent on them 2) An individual has 2 haplotypes of each set of genes (maternal/paternal) 3) MHC genes expressed codominantly (both maternal and paternal products) in same cells Class I MHC Proteins 1) Comprise 2 polypeptide chains 1. a chain (transmembrane)- encoded by MHC 2. b2 macroglobulin (encoded by highly conserved gene on different chromosome) 2) Folded molecule has 4 domains: a1, a2 (create peptide binding cleft), a3, b2 Class II MHC Proteins 1) Comprise 2 polypeptide chains 1. a chain 2) 2. b chain 3) Folded molecule has 4 domains: a1, a2, b1, b2 (transmembrane) 4) a1 and b1 domains comprise peptide binding cleft MHC Proteins 1) Peptide Binding Cleft: 2) Similar organisation on class I and II proteins 3) Floor of cleft is b sheet 4) Walls of cleft are a helices 5) Class I binding clefts are closed, class II are open 6) Peptides lie within the cleft in extended conformation Peptide Binding Clefts MHC Peptide Binding to Class I 1) Selective with high affinity to only certain peptides 2) Peptides are 8 - 9 residues long 3) Aliphatic/aromatic residues “anchor” peptide within the cleft 4) Anchor residues occur in all peptides binding a particular MHC class I molecule MHC Peptide Binding to Class I MHC Peptide Binding to Class II 1) Bind peptides in variable length from 12 to about 17 linearly arranged amino acids 2) Three (sometimes four) anchor residues in the central region of the peptide that bind to the allele‐ specific pockets of the MHC class II molecule 3) Class II proteins can bind greater range of peptides and anchor residues are more difficult to predict Self MHC Restriction 1) T cell can only recognise and respond antigenic peptide combining with MHC molecules 2) Helper T cells recognise antigen in context of class II self MHC 3) Cytotoxic T cells recognise antigen in context of class I self MHC Self MHC Restriction of Tc cells Tc cells kill only syngeneic virally infected target cells Both Tc cell and infected cell must share the Summary 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, with a peptide-binding groove that presents 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, essential for coordinating immune responses. 4. MHC restriction, is the principle that T cells recognise antigens only when they are presented by the body's own MHC molecules. This ensures that T cells respond specifically to cells presenting foreign antigens in the context of self- MHC, thus maintaining immune precision and preventing inappropriate immune activation.