Major Histocompatibility Complex

1
Major Histocompatibility Complex MHC Department
of Immunology Fudan University Bo GAO,
Ph.D 021-54237154 gaobo_at_fudan.edu.cn
2
Major Histocompatibilty Complex, MHC

• 1. Discovery of MHC
• MHC Genes
• Binding of Peptides to MHC Molecules
• MHC polymorphism
• Function and significance

3
  Types of graft
4
MHC of mice
1940s
Inbred mouse strains
H-2d H-2b
BALB/c
C57BL/6
Inbred mouse strains - all genes are identical
(George D. Snell)
5
Genetic basis of transplant rejection
Transplantation of skin between strains showed
that rejection or acceptance was dependent
upon the genetics of each strain
ACCEPTED
REJECTED
6
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.
7
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
leukocyte because the antibodies were tested by
binding to the leukocytes of other individuals,
and antigens because the molecules were
recognized by antibodies
Jean Dausset
8
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.
9
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
The relevant genes were called immune response
(Ir) genes, and they were all found to map to the
MHC
(Baruj Benacerraf )
10
Immune Response Genes
11
1980 Noble prize
(Baruj Benacerraf ) (Jean Dausset)(George D.
Snell)
12
Major Histocompatibilty Complex, MHC

• 1. Discovery of MHC
• MHC Genes
• Binding of Peptides to MHC Molecules
• MHC polymorphism
• Function and significance

13
MHC of human
MHC II
MHC III
MHC I
14
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.
15
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.
16
Expression
Why two types of polymorphic MHC genes are needed?
Nucleated cells
DC, B, MF
17
Expression
The expression of MHC molecules is increased by
cytokines produced during both innate and
adaptive immune responses.
IFN-a, IFN-ß , IFN-?
MHC I
MHC II
IFN-?
18
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-?
MHC I, MHC II
IFN-?
TAP, LMP2, LMP7
19
Structure
Crystal structures
Extracellular portions of MHC molecules.
MHC molecules with bound peptides
Important for us to understand how MHC molecules
display peptides
20
MHC-I
MHC- II
Peptide-binding cleft
Structure
a2
a1
b1
a1
Ig-like domain
a3
b2
b2m
a2
transmembrane domain
General Properties
Each MHC molecule consists of an extracellular
peptide-binding 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.
21
(No Transcript)
22
(No Transcript)
23
Major Histocompatibilty Complex, MHC

• 1. Discovery of MHC
• MHC Genes
• Binding of Peptides to MHC Molecules
• MHC polymorphism
• Function and significance

24
Characteristics of Peptide-MHC Interactions
1. Each class I or class II MHC molecule has a
single peptide-binding cleft that binds one
peptide at a time, but each MHC molecule can bind
many different peptides.
Why?
25
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
26
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.
27
Characteristics of Peptide-MHC Interactions
4. The association of antigenic peptides and MHC
molecules is a saturable interaction with a very
slow off-rate.
chaperones
MHC-peptide interaction
enzymes
Stable peptide-MHC complexes
Long half-lives
Maximize the chance that a particular T cell will
find the peptide
28
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..
29
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.
30
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?
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.
31
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?
32
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
33
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 ß strands of the floor and the a helices of
the walls of the cleft.
34
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 ß 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
35
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
36
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.
37
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
peptide-binding 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.
38
Structural Basis of Peptide-MHC Interactions
MHC I
MHC II
39
Major Histocompatibilty Complex, MHC

• 1. Discovery of MHC
• MHC Genes
• Binding of Peptides to MHC Molecules
• MHC polymorphism
• Function and significance

40
MHC polymorphism
In the human population
gene locus
Polymorphic alleles
multiple alleles co-dominant expression
41
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
42
The MHC possesses an extraordinarily large number
of different alleles at each locus
MHC I
MHC II
A B
C DRA DRB DQA1 DQB1 DPA1 DPB1
total Multiple allele 506 851 276
3 559 34 81 23 126
2581 MHC protein 28 62 10
24 9 6
1645
Up to 2007.03
Dw
43
Major Histocompatibilty Complex, MHC

• 1. Discovery of MHC
• MHC Genes
• Binding of Peptides to MHC Molecules
• MHC polymorphism
• Function and significance

44
Significance of MHC polymorphism
Bind to various Ag peptide Genetically determine
the immune responsiveness
Self-MHC restriction of T cell response
45
Rolf Zinkernagle Peter Doherty Nobel Prize 1996
46
T cell response is self-MHC restricted
47
Other function of MHC molecules
Individual marker Mediate transplantation
rejection
Association of MHC alleles with risk of disease
48
(No Transcript)
49
Other function of MHC molecules
Regulate the T cell development
50
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 b2-microglobulin. 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.