IL SISTEMA MAGGIORE DI ISTOCOMPATIBILITA

Transcription

1 IL SISTEMA MAGGIORE DI ISTOCOMPATIBILITA ENNIO CARBONE UNIVERSITA' DEGLI STUDI DI CATANZARO "MAGNA GRÆCIA Catanzaro KAROLINSKA INSTITUTET Microbiology and Tumor Biology Center MTC Stockholm

2 SCOPO DELLA LEZIONE FORNIRE INFORMAZIONI AGGIORNATE SUL SIGNIFICATO BIOLOGICO DELL MHC ANALIZZARE LA GENETICA E GLI ASPETTI MOLECOLARI DEL FUNZIONAMENTO DELL MHC LE MOLECOLE MHC CLASSICHE E NON CLASSICHE LORO FUNZIONI INTEGRARE CON UN SURVEY DELLA LETTERATURA RECENTE LE INFORMAZIONI OTTENIBILI DAI TESTI ADOTTATI

3 Struttura della lezione Definizione e significato biologico. Genetica del sistema maggiore di istocompatibilità. Struttura molecolare. Presentazione degli antigeni Riconoscimento da parte dei linfociti. MHC e Patologia

4 Only complementary surfaces fit together

5 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)

6 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

7 Nomenclature MHC = Major Histocombitibiliy 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

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 TCR MHC DC CD28 B7 2.) Cell to cell contact via soluble mediators such as cytokines (interleukins-il) or chemokines (CCR, CXCR) IFN-γ T cell TCR MHC DC CD28 B7 IL-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 Structure of MHC class I Computer graphic representation and ribbon diagramms of of the human MHC class I molecule HLA-A2. Heterodimer: α chain (43 kda): polymorphic β2-microglobin (12 kda): nonpolymorphic, non-covalently bound α1 and α2: peptide binding, cleft formed by single structure α3: transmembrane

12 MHC class II molecules present antigen originating in intracellular vesicles

13 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: α chain (34 kda) b-chain (29 kda) β1 and α1: peptide binding, not joined by covalent bond Α2 and b2 : transmembrane Peptide binding groove is the MHC class II molecules is open at both ends

14 MHC molecules on the cell surface display peptide fragments

15 Peptide binding sites and binding sites for CD4 or CD8 on MHC class I and MHC class II β chain (white) α Chain (white) α chain (purple) β2- Microglobuline (purple) Base of β2 domain (green) Base of α3 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 FUNZIONI DEL MHC

17 CROSS REATTIVITA

18 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.

19 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 A k allele, or human MHC II HLA-DR3 Peptides that bind to MHC class II are at least 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

20 BINDING SITE CONSERVATI IN TUTTE LE MOLECOLE MHC-I

21 REQUISITI MOLECOLARI PER IL BINDING DEI PEPTIDI CON LE MOLECOLE MHC-II

22 LEGAME PEPTIDE MOLECOLE MHC

23 Peptide presentation MHC-I QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

24 Peptide presentation MHC-II QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

25 QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

26 The peptide QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

27 THE EFFECT OF PEPTIDE LOADING b conformational eptide induced hanges QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

28 Peptide presentation requirement QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

29 La conformazione del peptide QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

30 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

31 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-γ.

32 T cells bearing a γδ T cell receptor γδt 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.

33 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-γ). IFN-γ also induces the key components of the intracellular machinery that enables peptides to be loaded onto MHC class I molecules

34 Genetic organisation of MHC

35 Simplified organisation of MHC in mouse and human

36 Evolution of the MHC genetic complex

37 IL POLIMORFISMO DEI GENI DELL MHC Gli alleli sono varianti molecolari della stessa sequenza genica Geni che posseggono varianti comuni all interno della popolazione Sono detti Polimorfici MHC classe I : HLA-A 95 alleli, HLA-B 207 alleli, HLA-C 50 alleli MHC classe II: HLA-DR, HLA-DQ, HLA-DP sono polimorfici Ogni individuo esprime 6 diversi geni HLA-Classe I e 6 diversi geni Per HLA-Classe II Queste caratteristiche dei geni HLA sono alla base del rigetto dei trapianti

38 PATTERN DI ESPRESSIONE DEI GENI MHC

39 CARATTERISTICHE GENICHE DEL MHC

40 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

41 GENE CONVERSION E POLIMORFISMO

42 RICOMBINAZIONE GENICA

43 Genetic organisation of the MHC Human chromosome 6 Mouse chromosome 17

44 IL SISTEMA MAGGIORE DI ISTOCOMPATIBILITA Polimorfico e Poligenico CROMOSOMA 6 UOMO,17 TOPO Grandezza 4 Centimorgan Contiene 200 geni

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

46 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)

47 MHC class I receptors on human Natural killer cells Receptors Ligands KIR receptors (Killer immunoglobulin receptors) HLA-C effect mostly inhib. NKG2A/CD94..HLA-E mostly inhib. NKG2D.MIC activ.

48 PRESENTAZIONE DI ANTIGENI NON PEPTIDICI MOLECOLE MHC LIKE

49 Structure of human CD1B

50 Antigen processing/presentation pathways and activation of different T-cell subsets

51

52 Properties of CD1B-presented antigens

53 Adaptor-protein complexes

54 Intracellular trafficking and steady-state distribution of human CD1 isoforms