The MHC complex: genetics, function and disease association

1. The MHC complex: genetics, function and disease association Lecturer: Adelheid Cerwenka, PhD, D080, Innate Immunity Sources: Janeway: Immunobiology, 5th edition Kuby: Immunology, 4th edition Klein/Horejsi:Immunology 2nd edition

2. “Innate Immunity”, D080

3. Only complementary surfaces fit together

4. MHC-structure Major Histocompatibility Complex (MHC): linked cluster of genes, which products play a role in intercellular recognition between self and nonself. The MHC is a region of multiple loci that play major roles in determining, whether transplanted tissue 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. Nomenclature • MHC = MajorHistocombitibiliy Complex • Minor Histocompatibility Antigens: proteins, which are cell surface expressed and their peptides are loaded into MHC molecules • MHC is a generic name • HLA = Human Leucocyte Antigen, eg SLA = Swine Leucocyte Antigen • Mouse: MHC has an historical name = H2 (H-2) stands for histocompatibility 2

7. Table of contents • Introduction • Structure of MHC I and II molecules • Genetic organisation of the MHC • Polymorphisms of MHC alleles • MHC and disease • Quiz

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) CD2 T cell DC MHC TCR CD28 B7 2.) Cell to cell contact via soluble mediators such as cytokines (interleukins-IL) or chemokines (CCR, CXCR) IFN-g T cell DC MHC TCR CD28 B7 IL-12

9. Host defense Against intracellular infection by mycobacteria Against intracellular infection by viruses

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 representation and ribbon diagramms of of the human MHC class I molecule HLA-A2. Heterodimer: a chain (43 kDa): polymorphic b2-microglobin (12 kDa): non-polymorphic, non-covalently bound a1 and a2: peptide binding, cleft formed by single structure a3: transmembrane

14. Structure of MHC class II Computer graphic representation and ribbon diagramms of of the human MHC class II molecule, HLA-DRI Heterodimer, 2 transmembrane chains: a chain (34 kDa) b-chain (29 kDa) b1 and a1: peptide binding, not joined by covalent bond A2 and b2 : transmembrane Peptide 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 of b2 domain (green) Base of a3 domain (green) The binding sites for CD4 and CD8 on MHC class II molecules or MHC class I lie 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 contacts Peptides 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 acids V, L and I are large hydrophobic amino acids MHC class I without peptide instable Pockets 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 peptide Peptides that bind to mouse MHC II Ak allele, or human MHC II HLA-DR3 Peptides that bind to MHC class II are at least 13-17 AA long, Ends of peptides are not conserved. Ends do not bind, binding pockets more permissive Blue: 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 cells MHC class II: Expressed on surface of APCs (antigen presenting cells) Viruses can infect all types of cells Plasmodia (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 B MHC class I expression can be regulated by Interferon (IFN-g). IFN-g also induces the key components of the intracellular machinery that enables 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 molecules • They 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 function • Peptides, that bind to MHC class I or II are derived of different compartments and are of different length • The expression of MHC class I molecules can be regulated by interferon-g.

22. Genetic organisation of MHC

23. Simplified organisation of MHC in mouse and human

24. Evolution of the MHC genetic complex

25. MHC diversity MHC is polygenic means that it contains several different MHC class I and class II genes MHC is polymorphic (poly=many Morphic=shape, structure): means that there are multiple variants of a gene within a population as a whole

26. Genetic organisation of the MHC Human chromosome 6 Mouse chromosome 17

27. Detailed map of the human MHC MHC class IB genes =Non-classical MHC Molecules =Non-conventional MHC Class I molecules

28. Function of non-conventional MHC molecules • Ligands of inhibitory (HLA-G) or activating (MIC) Natural Killer cell receptors • Presentation 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 effect KIR receptors (Killer immunoglobulin receptors)…HLA-C mostly inhib. NKG2A/CD94………………………..HLA-E mostly inhib. NKG2D……………………………….MIC activ.