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 = 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

7. Structure of MHC I and II molecules Genetic organisation of the MHC
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
TCR
MHC
CD28 B7
2.) Cell to cell contact via soluble mediators such as cytokines (interleukins-IL) or chemokines (CCR, CXCR)
IFN-g
T cell DC
TCR
MHC
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. 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 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
NKG2D……………………………….MIC activ.