4 MHC-structure Major Histocompatibility Complex (MHC): linked cluster of genes, which products play a role inintercellular recognition between self and nonself.The MHC is a region of multiple loci that playmajor roles in determining, whether transplantedtissue is accepted as self (histocompatible)or rejected as foreign (histoincompatible)
5 The concept of Histocompatibility A skin-graft transplanted from A donor to a genetically identical recipient is accepted, to a genetically disparate recipient is rejected
6 NomenclatureMHC = Major Histocombitibiliy ComplexMinor Histocompatibility Antigens: proteins, which are cell surface expressed and their peptides are loaded into MHC moleculesMHC is a generic nameHLA = Human Leucocyte Antigen, eg SLA = Swine Leucocyte AntigenMouse: MHC has an historical name = H2 (H-2) stands for histocompatibility 2
7 Structure of MHC I and II molecules Genetic organisation of the MHC Table of contentsIntroductionStructure of MHC I and II moleculesGenetic organisation of the MHCPolymorphisms of MHC allelesMHC and diseaseQuiz
8 Communication of cells in the body 1.) Cell cell contact via cell surface receptors:cell surface proteins have been classified as CDs(=cluster of differentiation)CD2T cellDCTCRMHCCD28B72.) Cell to cell contact via soluble mediators such as cytokines (interleukins-IL) or chemokines (CCR, CXCR)IFN-gT cellDCTCRMHCCD28B7IL-12
9 Host defense Against intracellular infection by viruses Against intracellular infection by mycobacteria
10 MHC class I molecules present antigen derived from proteins in the cytosol
11 MHC class II molecules present antigen originating in intracellular vesicles
12 MHC molecules on the cell surface display peptide fragments
13 Structure of MHC class I Computer graphic representationand ribbon diagramms ofof the human MHC class I moleculeHLA-A2.Heterodimer:a chain (43 kDa): polymorphicb2-microglobin (12 kDa): non-polymorphic, non-covalently bounda1 and a2: peptide binding, cleft formed by single structurea3: transmembrane
14 Structure of MHC class II Computer graphic representationand ribbon diagramms ofof the human MHC class II molecule, HLA-DRIHeterodimer, 2 transmembrane chains:a chain (34 kDa)b-chain (29 kDa)b1 and a1: peptide binding, not joined by covalent bondA2 and b2 : transmembranePeptide binding groove is the MHC class II molecules is open at both ends
15 Peptide binding sites and binding sites for CD4 or CD8 on MHC class I and MHC class II b chain (white)a-Chain (white)a chain(purple)b2-Microglobuline(purple)Base ofb2 domain(green)Baseof a3 domain(green)The binding sites for CD4 and CD8 on MHC class II molecules or MHC class Ilie in the immunoglobulin domain, nearest to the membrane
16 Peptides bind to MHC I molecules through structurally related anchor molecules Free amino and carboxy termini are stabilizing contactsPeptides eluted from two different MHC class I molecules are shown.Anchor residues in green:Not identical but related:eg: F and Y are both aromatic amino acidsV, L and I are large hydrophobic amino acidsMHC class I without peptide instablePockets in the MHC molecules are lined by polymorphic amino acids.
17 Peptides that bind MHC class II are variable in length and anchor residues lie at various distances from the ends of the peptidePeptides that bind to mouse MHC II Ak allele, or human MHC II HLA-DR3Peptides that bind to MHC class II are at least AA long,Ends of peptides are not conserved. Ends do not bind, binding pockets more permissiveBlue: negatively charged residue D, aspartic acid, E glutamic acid,green: hydrophobic residues
18 The expression of MHC molecules differs between tissues MHC class I:Expressed on all nucleated cellsMHC class II:Expressed on surface of APCs(antigen presenting cells)Viruses can infect all types of cellsPlasmodia (malaria)live in red blood cells
19 Regulation of MHC class I expression Expression of MHC class I regulated by sequences upstream of the coding part.MHC enhancer segment: enhancer A, IRE interferon response element, enhancer BMHC class I expression can be regulated by Interferon (IFN-g).IFN-g also induces the key components of the intracellular machinery thatenables peptides to be loaded onto MHC class I molecules
20 T cells bearing a gd T cell receptor gd T cells are not restricted by classical MHC moleculesThey may be specialized to bind certain types of ligands (heatshock proteins, mycobacterial lipid antigens) directly or presented by non-classical MHC molecules.
21 Conclusion: Structure of MHC molecules MHC class I and II molecules have different structure, different distribution on cells in the body, and different functionPeptides, that bind to MHC class I or II are derived of different compartments and are of different lengthThe expression of MHC class I molecules can be regulated by interferon-g.
25 MHC diversity MHC is polygenic means that it contains several different MHC class Iand class II genesMHC is polymorphic(poly=manyMorphic=shape, structure):means that there aremultiple variants of a gene withina population as a whole
26 Genetic organisation of the MHC Human chromosome 6Mouse chromosome 17
27 Detailed map of the human MHC MHC class IB genes=Non-classical MHCMolecules=Non-conventional MHCClass I molecules
28 Function of non-conventional MHC molecules Ligands of inhibitory (HLA-G) or activating (MIC) Natural Killer cell receptorsPresentation of non-conventional peptides to ?? Cells: In mice, the H-2M locus encodes a nonconventional MHC class I molecule that present peptides that have a formylated methionin (eg also found in prokaryotic organisms such as mycobacterium tuberculosis, listeria, Salmonella)Presentation of lipid antigens (CD1)
29 MHC class I receptors on human Natural killer cells Receptors……………………………Ligands effectKIR receptors(Killer immunoglobulin receptors)…HLA-C mostlyinhib.NKG2A/CD94………………………..HLA-E mostlyNKG2D……………………………….MIC activ.