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Chapter 7
Major Histocomptibility Complex (MHC)
Processing and presentation of
exogenous and endogenous antigens
Antigenic peptides recognized by T cells form trimolecular
complexes with a TCR and an MHC molecule
Class I MHC
peptide
Peptide
TCR
TC cell
CD8
TCR and MHC-peptide
TCR
 peptide
 MHC
1. MHC molecules act as antigen-presenting
structure.
2. MHC molecules expressed by an individual
influence the repertoire of antigens to which
that individual’s TH cells and TC vells can
respond.
3. MHC partly determines the response of an
individual to antigens of infectious organisms.
4. MHC has been implicated in the susceptibility
to disease and in the development of
autoimmunity.
本章大綱:
1. General Organization and Inheritance of the
MHC
2. MHC Molecules and Genes
3. Genomic Map of MHC Genes
4. Cellular Distribution of MHC Molecules
5. Regulation of MHC Expression
6. MHC and Immune Responsiveness
7. MHC and Disease Susceptibility
General Organization and
Inheritance of the MHC
Gorer (1930s):
1. Rejection of foreign tissue is the result of an
immune response to cell-surface molecules.
2. Identification of I, II, III and IV groups of genes.
Gorer and Snell (1940s & 1950s):
1. Antigens encoded by the genes in the group II took
part in the rejection of transplanted tumors and
other tissues.
2. Snell called these genes “histocompatibility genes”
(currently called H-2 genes)
3. Snell was awarded the Nobel Prize in 1980.
Human MHC: human leukocyte antigen
(HLA)
Mouse MHC: H-2
Class I MHC:
- Expressed on the surface of nearly all nucleated cells; the major
function of the class I gene products is presentation of peptide
Ags to CD8+ T cells.
Class II MHC:
- Expressed primarily on Ag-presenting cells (macrophages,
dendritic cells, and B cells), where they present processed
antigenic peptides to CD4+ T cells.
Class III MHC:
- Generally encode various secreted proteins that have immune
functions, including components of the complement system and
molecules involved in inflammation.
- The MHC loci are polymorphic:
Many alternative forms of the gene, or alleles, exist at
each locus.
- The MHC loci are closely linked.
The recombination frequency within the H-2 complex
is only 0.5%.
- Most individuals inherit the alleles encoded by these
closely linked loci as two sets, one from each parent.
Each set of alleles is referred to as a haplotype.
- The MHC alleles are codominantly expressed;
that is, both maternal and paternal gene products
are expressed in the same cells.
Inheritance of MHC haplotypes
Acceptance or rejection of skin grafts is controlled
by the MHC type of the inbred mice
Inheritance of HLA haplotype in a
hypothetical human family
Congenic MHC mouse strain
- Inbred mouse strains are syngeneic or identical at
all genetic loci.
- Two strains are congenic if they are genetically
identical except at a single locus or region.
- Congenic strains can be produced by a series of
crosses, backcrosses, and selections.
Production of congenic mouse strain
Strain A.B
Genetically identical to
strain A except for the
MHC locus or loci
contributed by strain B.
Examples of recombinant congenic mouse strains
generated during production of the B10.A strain from
parental strain B10 (H-2b) and parental strain A (H-2a)
MHC Molecules and Genes
Class I molecule
(45 kDa)
(12 kDa)
Class II MHC molecule
(33 kDa)
(28 kDa)
Class I and class II molecules
Class I a chain, class II a, b chains and b2M
are members of the Ig superfamily
3-D structure of the external domains of a
human class I HLA molecule based on x-ray
crystallographic analysis
Cleft: 25Å x 10Å x 11Å
can bind a peptide of 8-10 a.a.
Superimposition of the peptide-binding cleft
of class I and class II MHC molecules
Red: HLA-A2 (Class I)
blue: HLA-DR1 (Class II)
Organization of class I MHC gene
= K
Organization of class II MHC gene
= IAb
IAb
= IAa
IAa
Peptide binding by MHC molecules
- Peptide binding by class I and class II molecules does
not exhibit the fine specificity characteristic of Ag
binding by Ab and TCR.
- A given MHC molecule can bind numerous different
peptides, and some peptides can bind to several
different MHC molecules.
- The binding between a peptide and an MHC molecule
is often referred to as “promiscuous” (雜亂的).
Peptide-binding cleft is blocked
at both ends in class I molecules
8 – 10 amino acid residues, most commonly 9
Peptide-binding cleft is open
at both ends in class I molecules
13 – 18 amino acid residues
Binding affinity of MHC to peptides
- The association constant KD of the peptide-MHC
molecule complex is approximately 10-6.
- The rate of association is low, but the rate of
dissociation is even lower.
- Thus, the peptide-MHC molecule association is very
stable under physiological conditions and most of the
MHC molecules expressed on the membrane of a cell
are associated with a peptide of self or nonself origin.
Class I MHC molecules bind peptides
and present them to CD8+ T cells
– cytosolic or endogenous processing pathway
Anchor residues in nonameric (9) peptides eluted
from two class I MHC molecules
Usually
hydrophobic
Two different nonamers
can bind to the same H-2kb
Vesicular stomatitis
virus (VSV-8) peptide
Sendai virus
(SEV-9) nucleoprotein
Conformational difference in bound
peptides of different lengths
Molecular models based on crystal structure of an
influenza virus antigenic peptide and an endogenous
peptide bound to a class I MHC molecule
influenza virus
endogenous
a1 and a2 domains of HLA-B27 and a
bound antigenic peptide
peptide
water molecule
Class II MHC molecules bind peptides
and present them to CD4+ T cells
– endocytic or exogenous processing pathway
Peptide-binding cleft is open
at both ends in class I molecules
13-18 a.a. residues
A central core of 13 a.a. determines the
ability of a peptide to bind class II.
Polymorphism of class I and class II molecules
- The diversity of the MHC within a species stems from
polymorphism, the presence of multiple alleles at a given
genetic locus within the species.
- The MHC possesses an extraordinarily large number of
different alleles at each locus and is one of the most
polymorphic genetic complexes known in higher vertebrates.
HLA-A 60 alleles
HLA-B 110 alleles
HLA-C 40 alleles
H-2K
H-2D
55 alleles
60 alleles
- The theoretical diversity possible for the mouse is:
100 (K) x 100 (IAa) x 100 (IAb) x 100 (IEa) x 100 (IEb) x 100 (D) = 1012
Linkage disequilibrium
Certain allelic combinations occur more frequently
than predicted is referred to as linkage disequilibrium.
[Hypothesis]:
1. Sufficient numbers of generations have not elapsed.
2. Certain combinations of alleles are beneficial to the
individuals.
3. Crossovers are more frequent in certain DNA sequence
regions than in others.
Variability in the amino acid sequence
of allelic class I MHC molecules
Location of polymorphic amino acid residues
Most of the
residues with
significant
polymorphism
are located in the
peptide-binding
cleft
Class III molecules are not membrane
proteins, are not related structurally to
class I and class II molecules, and have
no role in Ag presentation, although most
play some role in immune responses.
e.g., C2, C4a, C4b, factor B, 21-hydroxylase enzymes,
TNFa, TNFb, heat shock proteins (HSP)
Genetic Map of MHC Genes
Mouse H-2 is on the chromosome 17
Class I
Nonclassical
Class II
Class III
Class I
Nonclassical
Human HLA is on the chromosome 6
Class II
Nonclassical
Class II
Class III
Class I
Nonclassical
Cellular Distribution of
MHC Molecules
Cellular distribution of
MHC class I molecules
- In general, the classical MHC class I molecules are
expressed on most somatic cells.
- The highest level of class I molecules are expressed on
lymphocytes: 1 % of the total plasma membrane proteins
or 5 x 105 molecules / cell.
- Fibroblasts, muscle cells, hepatocytes and neural cells
express very low levels of class I molecules.
- A few cell types (e.g., neurons and sperm cells at certain
stages of differentiation) appear to lack class I MHC
molecules altogether.
Cellular distribution of
MHC class II molecules
- Class II molecules are expressed constitutively only by
Ag-presenting cells (APC), e.g., macrophages, dendritic
cells, and B cells.
- Thymic epithelial cells and some other cell types can be
induced to function as APC and then express class II
molecules under certain conditions.
Various MHC molecules expressed on
APC of a heterozygous H-2k/d mouse
Nonclassical MHC class I and class II molecules
- Structurally similar to class I or class II molecules
- Less polymorphic
- Expressed at lower level
- Tissue distribution is more limited
- Functions not clear
The End