The MHC complex: genetics, function and disease association Lecturer: Adelheid Cerwenka, PhD, D080,...

The MHC complex: genetics, function and disease association

Lecturer: Adelheid Cerwenka, PhD, D080, Innate Immunity

Sources: Janeway: Immunobiology, 5th editionKuby: Immunology, 4th editionKlein/Horejsi:Immunology 2nd edition

“Innate Immunity”, D080

Only complementary surfaces fit together

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)

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

• 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

Nomenclature

• Introduction

• Structure of MHC I and II molecules

• Genetic organisation of the MHC

• Polymorphisms of MHC alleles

• MHC and disease

• Quiz

Table of contents

1.) Cell cell contact via cell surface receptors:cell surface proteins have been classified as CDs (=cluster of differentiation)

CD2

DCT cellMHCTCR

B7CD28

2.) Cell to cell contact via soluble mediators such as cytokines (interleukins-IL) or chemokines (CCR, CXCR)

DCT cellMHCTCR

B7CD28

IL-12

IFN-

Communication of cells in the body

Host defense

Against intracellular infection by viruses Against intracellular infection by mycobacteria

MHC class I molecules present antigen derived from proteins in the cytosol

MHC class II molecules present antigen originating in intracellular vesicles

MHC molecules on the cell surface display peptide fragments

Structure of MHC class I

Computer graphic representationand ribbon diagramms of of the human MHC class I moleculeHLA-A2.

Heterodimer: chain (43 kDa): polymorphic2-microglobin (12 kDa): non-polymorphic, non-covalently bound

1 and 2: peptide binding, cleft formed by single structure3: transmembrane

Structure of MHC class II

Computer graphic representationand ribbon diagramms of of the human MHC class II molecule, HLA-DRI

Heterodimer, 2 transmembrane chains: chain (34 kDa)b-chain (29 kDa)

1 and 1: peptide binding, not joined by covalent bond2 and b2 : transmembrane

Peptide binding groove is the MHC class II molecules is open at both ends

Peptide binding sites and binding sites for CD4 or CD8 on MHC class I and MHC class II

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

Base of2 domain(green)

chain(purple)

chain (white)

2-Microglobuline(purple)

Chain (white)

Base of 3 domain(green)

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.

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-DR3Peptides 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 permissiveBlue: negatively charged residue D, aspartic acid, E glutamic acid, green: hydrophobic residues

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 cellsPlasmodia (malaria)live in red blood cells

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

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.

T cells bearing a T cell receptor

• 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-.

Conclusion: Structure of MHC molecules

Genetic organisation of MHC

Simplified organisation of MHC in mouse and human

Evolution of the MHC genetic complex

MHC diversity

MHC is polygenicmeans that it containsseveral different MHC class I and class II genes

MHC is polymorphic(poly=manyMorphic=shape, structure):

means that there are multiple variants of a gene within a population as a whole

Genetic organisation of the MHC

Mouse chromosome 17

Human chromosome 6

Detailed map of the human MHC

MHC class IB genes=Non-classical MHC Molecules=Non-conventional MHC Class I 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)

Function of non-conventional MHC molecules

MHC class I receptors on human Natural killer cells

Receptors……………………………Ligands effectKIR receptors (Killer immunoglobulin receptors)…HLA-C mostly inhib.

NKG2A/CD94………………………..HLA-E mostly inhib.NKG2D……………………………….MIC activ.