The major histocompatibility complex (MHC) and MHC molecules

The major histocompatibility complex (MHC) and MHC molecules 1. Introduction 2. Human MHC organization and genetic features 3. The MHC molecules 4. Functions of MHC molecules 5. Applications of MHC study

1. Introduction MHC was initially identified in graft rejection Histocompatibility: the acceptance or tolerance between tissues of donor and recipient. Major histocompatibility antigens: a group of antigens (cell surface proteins) primarily responsible for the rapid rejection of grafts between individuals

The MHC was found to be important in graft survival

T cells recognise antigens in the context of MHC molecules The recognition of antigen by T cell is the initial step for adaptive immune response. T cells can only be activated by interaction between the antigen receptor and peptide antigen in an MHC molecule

Antigen recognition by T cells requires peptide antigens and presenting cells that express MHC molecules

MHC A cluster of tightly linked genes whose products function in presenting antigen (antigenic peptides) for T cell to recognize, and are primarily responsible for the rapid rejection of grafts between individuals MHC has been identified in all mammalian species MHC in human: HLA, whose products are HLA molecules (antigens) MHC in mice: H-2, whose products are H-2 molecules (antigens)

2. MHC in human  HLA (human leukocyte antigen) 2.1. Genomic organization Human MHC is located on the short arm of the 6th chromosome comprises over 200 loci Based on the structure and functions of their products, these gene loci are classified into 2 categories

2.1.1. Classical HLA class I and HLA class II loci The products of these gene loci are able to present antigen, and show extreme polymorphism HLA class I loci HLA-A, -B, -C HLA class II loci HLA-DR, -DQ, -DP

Immunologically irrelevant genes 2.1.2. Other genes in the MHC MHC Class 1b genes Encoding MHC class I-like proteins that associate with  2 microglobulin: HLA-G binds to CD94 (NK-cell receptor). Inhibits NK cell attack of foetus/ tumours HLA-E binds conserved leader peptides from HLA-A, B, C. Interacts with CD94 HLA-F function unknown MHC Class II genes Encoding several antigen processing genes: HLA-DM  and , proteasome components (LMP-2 & 7), peptide transporters (TAP-1 & 2), HLA-DO  and DO  MHC Class III genes Encoding complement proteins C4, C2 and Factor B, TNF- and  Immunologically irrelevant genes Genes encoding 21-hydroxylase, RNA Helicase, Caesin kinase Heat shock protein 70,

Map of human MHC

2.2. Genetic features of HLA 2.2.1. Polymorphism 2.2.2. Inheritance of MHC haplotypes

Polymorphism in the MHC Variation >1% at a single genetic locus in a population of individuals Each polymorphic variant is called an allele In the human population, over 1,200 MHC alleles have been identified. MHC genes are the most polymorphic known

Inheritance of MHC haplotypes The combination of alleles on a chromosome is an MHC HAPLOTYPE Genes in the MHC are tightly linked and usually inherited in a group (haplotype)

3. The MHC products — the MHC molecules 3.1. Structure of MHC class I and Class II molecules 3.2. Expression of MHC class I and class II molecules

3.1.1 Structure of MHC class I molecules A heterodimer comprises an -chain (heavy chain, 43kDa) and a 2-microglobulin (light chain, 12kDa). MHC-encoded -chain of is polymoephic, and anchored to the cell membrane Peptide antigen-binding groove formed by the 1 and 2 domains of the heavy chain, where the polymorphic residues are. CD8-binding site formed by 3 domain & 2m, which have structural & amino acid sequence homology with Ig C domains (Ig gene superfamily).

The structure of an MHC class I molecules (determined by X-ray crystallography) Panel A: computer graphic representation of HLA-A2, cleaved from the cell surface by the enzyme papain. Panel B: a ribbon diagram of that structure Panel C: looking down on the molecule from above, the sides of the cleft are formed from the inner faces of the 2  helics, the  pleated sheet creates the floor of the cleft. Panel D: schematic structure MHC class I molecule is a heterodmer of a  chain (43000 Da, membrane-spanning ) non-covalently associated with a 2-microglobulin ( 12000Da, not spanning the membrane)  chain folds into 3 domains:1, 2, 3 1, 2 domains fold together into a single structure consisting of 2 segmented  helics lying on a sheet of eight anti-parallel  strands. The folding of the 1, 2 domains creates a long cleft or groove, which is the site at which antigen peptide bind to the MHC molecules. 33 and 2-microglobulin show similarities in amino acid sequence and folded structures to Ig constant region. The domains are colored according to the domains

3.1.2. Structure of MHC class II molecules A heterodimer comprises an -chain (34kDa) and a -chain (29kDa), both are MHC-encoded (polymorphic), and are anchored to the cell membrane Peptide antigen-binding groove formed 1 and 1domains, where the polymorphic residues are. CD4-binding site formed by 2 & 2 domains where have structural & amino acid sequence homology with Ig C domains (Ig gene superfamily).

The structure of an MHC class II molecules (resemble MHC class I molecules in structure) Panel A: computer graphic of the structure of the MHC class II molecule (protein HLA-DR1 in this case). Panel B: the equivalent ribbon diagram. Panel C: top view of the peptide binding groove, which is more open at both ends.: Panel D: schematic structure . MHC class II molecule is composed of 2 transmembrane glycoprotein chains,  (34000Da) and  (29000Da), both are encoded by MHC class II genes. Both chains folds into 2 domains:1, 2 of  chain, 1, 2 domains f  chain. The antigen peptide binding cleft are contributed by 1 and 1 domains of different chains. The 2, 2 domains have amino acid sequence and structural similarities to Ig constant domain.

3.2. Expression of MHC molecules MHC class I molecules are expressed by almost all nucleated cells of the body. MHC class II molecules are mainly expressed by antigen-presenting cells, eg. dendritic cells, B cells and macrophages.

Expression of MHC molecules differs between tissues 1. MHC class I are expressed on all nucleated cells, they are highly expressed in hematopoietic cells (upper panel) 2. MHC class II are normally expressed only by a subset of hematopoietic cells and thymus stromal cells, although they may be expressed by other cell types on exposure to the inflammatory cytokine interferon- * In humans, activated T cells express MHC class II molecules, whereas in mice, all T cells are MHC class II- negative. ^ In the brain, most cell types are MHC class II-negative but microglia, which are related to marophages, are MHC class II-positive.

4. Biological functions of MHC 4.1. Antigen-presenting for T cell recognition Peptide antigen-binding groove of MHC molecules binds antigenic peptides  MHC peptide complex T cell recognition and initiation of adaptive response MHC class I molecules present endogenous antigens to CD8+ T cells MHC class I molecules present exogenous antigens to CD4+ T cells

MHC molecules present antigenic peptides for T cells to recognise

TCR recognizes both antigenic peptide and MHC molecule  MHC restricted recognition

4.2. Other functions associated with antigen-presenting MHC alleles control the immune responsiveness The structure of MHC molecules is directly related to their function in antigen presentation, for allelic antigen-binding groove binds a unique set of antigenic peptides involved in T cell development in thymus

MHC alleles control the immune responsiveness

Polymorphic residues are located in the antigen-binding groove — Variation in amino acid sequences changes the shape of the groove

5. Clinically relevant applications of MHC 1. Matching of transplant donors and recipients 2. The association of MHC polymorphism with diseases MHC alleles affect the resistance or susceptibility to diseases, eg. Individual with HLA-B27 is more likely to have ankylosing spondylitis 3. The association of MHC expression with diseases Tumor cells express no or less MHC class I molecules in order to escape from the attack by T cells The isolet cells of IDDM patients are found to express MHC class II molecules 4. Forensic and anthropology studies

Summary • T cells recognise antigens in the context of MHC molecules • MHC molecules bind to peptide antigens, and present the peptides for T cell recognition • The structure of MHC molecules is directly related to their function in antigen presentation • Polymorphism and polygenism in the MHC protects the population from pathogens evading the immune system