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
“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
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
Table of contents
• Introduction
• Structure of MHC I and II molecules
• Genetic organisation of the MHC
• Polymorphisms of MHC alleles
• MHC and disease
• Quiz
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
MHC
TCR
CD28
IL-12
B7
DC
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 representation
and ribbon diagramms of
of the human MHC class I molecule
HLA-A2.
Heterodimer:
a chain (43 kDa): polymorphic
b2-microglobin (12 kDa): nonpolymorphic, non-covalently bound
a1 and a2: peptide binding, cleft
formed by single structure
a3: transmembrane
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
Peptide binding sites and binding sites for CD4 or
CD8 on MHC class I and MHC class II
b chain (white)
a chain
(purple)
Base of
b2 domain
(green)
aChain (white)
b2Microglobuline
(purple)
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
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-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
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
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
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 nonclassical MHC molecules.
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.
Genetic organisation of MHC
Simplified organisation of MHC in mouse and
human
Evolution of the MHC genetic complex
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
Genetic organisation of the MHC
Human chromosome 6
Mouse chromosome 17
Detailed map of the human MHC
MHC class IB genes
=Non-classical MHC
Molecules
=Non-conventional MHC
Class I molecules
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)
MHC class I receptors on human Natural killer cells
Receptors……………………………Ligands
KIR receptors
(Killer immunoglobulin receptors)…HLA-C
NKG2A/CD94………………………..HLA-E
NKG2D……………………………….MIC
effect
mostly
inhib.
mostly
inhib.
activ.