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INSTITUTE FOR IMMUNOBIOLOGY
Major Histocompatibility Complex
MHC
Department of Immunology
Fudan University
Bo GAO, Ph.D
021-54237154
[email protected]
Major Histocompatibilty Complex, MHC
1. Discovery of MHC
2. MHC Genes
3. Binding of Peptides to MHC
Molecules
4. MHC polymorphism
5. Function and significance
Types of graft
MHC of mice
1940s
Inbred mouse strains
H-2d
BALB/c
（George D. Snell)
H-2b
C57BL/6
Inbred mouse strains - all genes are identical
Genetic basis of transplant rejection
Transplantation of skin between strains showed that
rejection or acceptance was dependent upon
the genetics of each strain
ACCEPTED
Skin from an inbred mouse grafted onto the same strain of mouse
REJECTED
Skin from an inbred mouse grafted onto a different strain of mouse
MHC of mice
H-2 ( Histocompatibility-2)
A single genetic region is identified by Snell's group,
which is primarily responsible for rapid rejection of
tissue grafts, and this region was called the major
histocompatibility locus.
The particular locus encodes a blood group antigen
called antigen II, and therefore this region was named
histocompatibility-2, or simply H-2.
MHC of human
HLA ( Human leukocyte antigen)
Discovered by searching for cell surface
molecules in one individual that would be
recognized as foreign by another
individual
Jean Dausset
leukocyte because the antibodies were
tested by binding to the leukocytes of
other individuals, and antigens because
the molecules were recognized by
antibodies
HLA proteins and the mouse H-2 proteins had essentially
identical structure.
Genes encoding HLA are homologous to the H-2 genes.
They are all called MHC genes.
Immune Response Genes
Inbred strains of guinea pigs and mice
differed in their ability to make antibodies
against some simple synthetic polypeptides
Responsiveness was inherited as a dominant
mendelian trait
(Baruj Benacerraf )
The relevant genes were called immune
response (Ir) genes, and they were all
found to map to the MHC
Immune Response Genes
These immune response (Ir) genes, are,
in fact, MHC genes that encode MHC
molecules that differ in their ability to
bind and display peptides derived from
various protein antigens.
1980 Noble prize
(Baruj Benacerraf ) （Jean Dausset）（George D. Snell)
Major Histocompatibilty Complex, MHC
1. Discovery of MHC
2. MHC Genes
3. Binding of Peptides to MHC
Molecules
4. MHC polymorphism
5. Function and significance
MHC of human
MHC II
MHC III
MHC I
Expression
Because MHC molecules are required to present antigens
to T lymphocytes, the expression of these proteins in a cell
determines whether foreign (e.g., microbial) antigens in
that cell will be recognized by T cells.
There are several important features of the expression of
MHC molecules that contribute to their role in protecting
individuals from diverse microbial infections.
Expression
Class I molecules are constitutively expressed on
virtually all nucleated cells.
Class II molecules are expressed only on
dendritic cells, B lymphocytes, macrophages, and
a few other cell types.
Expression
Why two types of polymorphic MHC genes are needed?
DC, B, MΦ
Nucleated
cells
Expression
The expression of MHC
molecules is increased by
cytokines produced during
both innate and adaptive
immune responses.
IFN-α, IFN-β
, IFN-γ
IFN-γ
MHC I
MHC II
Expression
The rate of transcription is the major determinant of the
synthesis of MHC molecule and its expression on the
cell surface.
Class II transcription activator (CIITA): highly inducible by IFN-γ
MHC I, MHC II
IFN-γ
TAP, LMP2, LMP7
Structure
Crystal structures
Extracellular portions of MHC molecules.
MHC molecules with bound peptides
Important for us to understand how MHC molecules
display peptides
MHC-I
Structure
General Properties
MHC- II
a2
a1
a1
b1
Peptide-binding
cleft
a3
b2 m
a2
b2
Ig-like domain
transmembrane
domain
Each MHC molecule consists of an extracellular peptidebinding cleft, or groove, followed by immunoglobulin (Ig)-like
domains and transmembrane and cytoplasmic domains.
The polymorphic amino acid residues of MHC molecules are
located in and adjacent to the peptide-binding cleft.
The nonpolymorphic Ig-like domains of MHC molecules
contain binding sites for the T cell molecules CD4 and CD8.
Major Histocompatibilty Complex, MHC
1. Discovery of MHC
2. MHC Genes
3. Binding of Peptides to MHC
Molecules
4. MHC polymorphism
5. Function and significance
Characteristics of Peptide-MHC Interactions
1. Each class I or class II MHC molecule has a single peptidebinding cleft that binds one peptide at a time, but each MHC
molecule can bind many different peptides.
Why?
Each individual contains only a few different MHC
molecules (6 class I and more than 10 to 20 class II molecules in a
heterozygous individual)
Characteristics of Peptide-MHC Interactions
2. The peptides that bind to MHC molecules share
structural features that promote this interaction.
MHC I: 8 to 11 residues
MHC II: 10 to 30 residues (optimal length 13 to 18)
Complementary interactions between the peptide and that
allelic MHC molecule
The residues of a peptide that bind to MHC molecules are
distinct from those that are recognized by T cells
Characteristics of Peptide-MHC Interactions
3. MHC molecules acquire their peptide cargo during
their biosynthesis and assembly inside cells.
MHC molecules display peptides derived from microbes
that are inside host cells
MHC-restricted T cells recognize cell-associated microbes.
They are the mediators of immunity to intracellular microbes.
Characteristics of Peptide-MHC Interactions
4. The association of antigenic peptides and MHC
molecules is a saturable interaction with a very slow offrate.
chaperones
enzymes
MHC-peptide interaction
Stable peptide-MHC complexes
Maximize the chance that a particular T
cell will find the peptide
Long half-lives
Characteristics of Peptide-MHC Interactions
5. Very small numbers of peptide-MHC complexes are
capable of activating specific T lymphocytes.
As few as 100 complexes of a particular peptide with a class
II MHC molecule on the surface of an APC can initiate a
specific T cell response.
This represents less than 0.1% of the total number of class II
molecules likely to be present on the surface of the APC..
Characteristics of Peptide-MHC Interactions
6. The MHC molecules of an individual do not discriminate
between foreign peptides and peptides derived from self
antigens.
MHC molecules display both self peptides and foreign peptides.
Most of peptides displayed by APCs derive from self proteins.
Characteristics of Peptide-MHC Interactions
Question 1:
How can a T cell recognize and be activated by any
foreign antigen if normally all APCs are displaying
mainly self peptide-MHC complexes?
Answer:
T cells are remarkably sensitive and need to specifically
recognize very few peptide-MHC complexes to be activated.
Thus, a newly introduced antigen may be processed into
peptides that load enough MHC molecules of APCs to activate T
cells specific for that antigen, even though most of the MHC
molecules are occupied with self peptides.
Question 2:
If individuals process their own proteins and present them
in association with their own MHC molecules, why do we
normally not develop immune responses against self
proteins?
Answer:
T cells specific for such complexes are killed or
inactivated. Therefore, T cells cannot normally respond to
self antigens
Structural Basis of Peptide-MHC Interactions
The binding of peptides to MHC molecules is a
noncovalent interaction mediated by residues both in the
peptides and in the clefts of the MHC molecules.
Anchor residue
Anchor pocket
Structural Basis of Peptide-MHC Interactions
These peptides bind to the clefts of MHC molecules in an
extended conformation. Once bound, the peptides and their
associated water molecules fill the clefts, making extensive
contacts with the amino acid residues that form the β strands of
the floor and the α helices of the walls of the cleft.
Structural Basis of Peptide-MHC Interactions
In the case of MHC I, association of a peptide with the MHC
groove depends on the binding of the positively charged N
terminus and the negatively charged C terminus of the peptide
to the MHC molecule. In most MHC molecules, the β strands in
the floor of the cleft contain "pockets."
Many class I molecules have a hydrophobic pocket that
recognizes one of the following hydrophobic amino acids-valine,
isoleucine, leucine, or methionine-at the C-terminal end of the
peptide.
Anchor pocket
Structural Basis of Peptide-MHC Interactions
Such residues of the peptide are called anchor residues because
they anchor the peptide in the cleft of the MHC molecule. Each
MHC-binding peptide usually contains only one or two anchor
residues, and this presumably allows greater variability in the
other residues of the peptide, which are the residues that are
recognized by specific T cells.
The 2 and 9 anchor residue play
critical roles
Structural Basis of Peptide-MHC Interactions
Many of the residues in and around the peptide-binding
cleft of MHC molecules are polymorphic and different
alleles favor the binding of different peptides.
This is the structural basis for the function of MHC
genes as "immune response genes";
Only animals that express MHC alleles that can bind a
particular peptide and display it to T cells can respond to
that peptide.
Structural Basis of Peptide-MHC Interactions
The antigen receptors of T cells recognize both the
antigenic peptide and the MHC molecules, with the
peptide being responsible for the fine specificity of
antigen recognition and the MHC residues accounting for
the MHC restriction of the T cells.
Variations in either the peptide antigen or the peptidebinding cleft of the MHC molecule will alter
presentation of that peptide or its recognition by T cells.
In fact, one can enhance the immunogenicity of a
peptide by incorporating into it a residue that strengthens
its binding to commonly inherited MHC molecules in a
population.
Structural Basis of Peptide-MHC Interactions
MHC I
MHC II
Major Histocompatibilty Complex, MHC
1. Discovery of MHC
2. MHC Genes
3. Binding of Peptides to MHC
Molecules
4. MHC polymorphism
5. Function and significance
MHC polymorphism
In the human population
gene locus
Polymorphic alleles
multiple alleles
co-dominant expression
MHC polymorphism
Co-dominance
polygeny
Diversity of MHC molecules
Co-dominance and polygeny both
contribute to the diversity of MHC
molecules expressed by an individual
The MHC possesses an extraordinarily large number
of different alleles at each locus
MHC I
A
B
C
Multiple allele 506 851 276
MHC protein
* Up to 2007.03
28
62
10
MHC II
DRA DRB DQA1 DQB1 DPA1 DPB1
3
559
24
34
81
9
23
126
6
total
2581
1645
Major Histocompatibilty Complex, MHC
1. Discovery of MHC
2. MHC Genes
3. Binding of Peptides to MHC
Molecules
4. MHC polymorphism
5. Function and significance
Significance of MHC polymorphism
Bind to various Ag peptide
Genetically determine the immune responsiveness
Self-MHC restriction of T cell response
Rolf Zinkernagle
Peter Doherty
Nobel Prize 1996
T cell response is self-MHC restricted
Other function of MHC molecules
Individual marker
Mediate transplantation rejection
Association of MHC alleles with risk of disease
Other function of MHC molecules
Regulate the T cell development
SUMMARY
The major histocompatibility complex (MHC) comprises a stretch of
tightly linked genes that encode class I/II proteins associated with
intercellular recognition and antigen presentation to T lymphocytes.
MHC genes are polymorphic in that there are large numbers of alleles for
each gene, and they are polygenic in that there are a number of different
MHC genes.
Class I MHC molecules consist of an a chain, in complex with b2microglobulin.
Class II MHC molecules are composed of two noncovalently associated
glycoproteins, the a and b chain, encoded by separate MHC genes.
Both class I and class II MHC molecules present antigen to T cells. Class
I molecules present processed endogenous antigen to CD8+ T cells.
Class II molecules present processed exogenous antigen to CD4+ T
cells.
Class I molecules are expressed on most nucleated cells; class II
antigens are restricted to B cells, macrophages, and dendritic cells.