Chapter 7

Major Histocomptibility Complex (MHC)

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

Processing and presentation of

exogenous and endogenous antigens

45kDa

12kDa

33kDa

28kDa

1. MHC molecules act as antigen-presenting

structure.
2. MHC molecules expressed by an individual
influence the repertoire of antigens to which
that individuals TH cells and TC cells 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.

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

(chromosome 17)

(chromosome 6)

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.

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- 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

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

45kDa

12kDa

33kDa

28kDa

Class I chain, class II , chains and 2M

are members of the Ig superfamily

Help surface expression

Conserved

MHC class I

Cleft: 25 x 10 x 11
can bind a peptide of 8-10 a.a.

crystallized dimer

MHC class II

Superimposition of the peptide-binding cleft

of class I and class II MHC molecules

Superimposition of the peptide-binding cleft

of class I and class II MHC molecules

Organization of class I MHC gene

= K

Organization of class II MHC gene

= IA

IA

= IA

IA

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 ().

Two different nonamers

can bind to the same H-2kb

Vesicular stomatitis
virus (VSV-8) peptide

Sendai virus
(SEV-9) nucleoprotein

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.

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

Class I MHC molecules bind peptides

and present them to CD8+ T cells

105 copies of each MHC class I /cell

cytosolic or endogenous processing pathway

Anchor residues in nonameric (9) peptides eluted

from two class I MHC molecules
Usually
hydrophobic

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

1 and 2 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
HLA-B
HLA-C

240 alleles
470 alleles
110 alleles

H-2K
H-2D

55 alleles
60 alleles

-The theoretical class I diversity possible for the human is

240x470x110

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

The diversity in Class II MHC are located at

1 and 1 domain.

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.

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,
TNF, TNF, heat shock proteins (HSP)