Major Histocompatibility

Complex
 Major Histocompatibility
Complex: History
• Transplantation: graft rejection

• Highly polymorphic
• Bind peptide: recognized by T cells
 Major Histocompatibility
Complex (MHC)
• MHC are peptide receptors that bind short
antigenic peptides on the surface of antigen
presenting cells and present them to the T-cell
receptors on the cell surface.
• 2 classes are distinguished: Class I and Class II.
• High diversity.
• MHC-peptide binding is allele specific.
 Structure of Class I MHC
α1
NH2
NH2
Alloantigenic
sites β2
NH2

α2 COOH
CHO

α3 Disulfide bridge

Papain cleavage

Plasma membrane

OH P
Cytoplasm
COOH
 Structure of Class I MHC
• Two polypeptide chains, a long α chain and a short
β chain, called β2 microglobulin
• Four regions:
1. Peptide-binding region - a groove formed from α1
and α2 domains of the α chain
2. Immunoglobulin-like region – highly conserved α3
domain - site to which CD8 on T cell binds
 Structure of Class I MHC
(continued)
3. Transmembrane region – stretch of
amino acids spanning membrane
4. Cytoplasmic region – contains sites
for phosphorylation
 Structure of Class I MHC
α1
NH2
NH2
Alloantigenic
sites β2
NH2

α2 COOH
CHO

α3 Disulfide bridge

Papain cleavage

Plasma membrane

OH P
Cytoplasm
COOH
 Structure of Class I MHC
Peptide-binding Region
• a “groove” composed of an α-helix on two opposite
walls and eight β-pleated sheets forming the floor
• residues lining groove most polymorphic
• peptide in groove 8-10 amino acids long
• specific amino acid on peptide required for “anchor
site” in groove
 Structure of Class II MHC
• Two polypeptide chains, α and β, of roughly equal
length.
• Four regions:
1. Peptide-binding region – a groove formed from the
α1 and β1 domains of the α and β chains – site of
polymorphism
2. Immunoglobulin-like region – conserved α2 and β2
domains – β2 is site to which CD4 on T cell binds
 Structure of Class II MHC
(continued)
3. Transmembrane region – stretch of
hydrophobic amino acids spanning
membrane
4. Cytoplasmic region – contains sites
for phosphorylation
Structure of Class II MHC
NH2 NH2

CHO α1 β1 CHO

CHO α2 β2

Plasma membrane

Cytoplasm
COOH COOH
Structure of Class II MHC
NH2 NH2

CHO α1 β1 CHO

CHO α2 β2

Plasma membrane

Cytoplasm
COOH COOH
Peptide-binding grooves for class I
and class II MHC are structurally
similar
• Both have a peptide-binding groove with a wall of
two α helices and a floor of eight β-pleated sheets
• Close-ended groove for class I MHC requires an
8-10 amino acid-length peptide to bind; open-
ended groove for Class II MHC lets it bind a
peptide 13-25 amino acids long, not all of which
lie in the groove
• Anchor site rules apply to both classes
• MHC class I and class II molecules differentially
bind CD8 and CD4 cell adhesion molecules.
• MHC class I molecules specifically bind CD8
molecules expressed on cytotoxic T
lymphocytes(Tc).
• MHC class II molecules specifically bind CD4
molecules expressed on helper T lymphocytes(Th)
 Aspects of MHC
1. MHC molecules are membrane-bound.
Recognition by T cells requires cell-cell
contact.
2. Endogenous antigen associates with class
I MHC and is recognized byCD8+ Tc cells.
Exogenous antigen associates with class
II MHC and is recognized by CD4+Th
cells.
Aspects of MHC (continued)

A peptide must associate with a given

MHC of that individual, otherwise no
immune response can occur. That is
one level of control.
Aspects of MHC (continued)
4. Mature T cells must have a T cell
receptor that recognizes the peptide
associated with MHC. This is the
second level of control.
5. Each MHC molecule has only one
binding site. The different peptides a
given MHC molecule can bind all
bind to the same site, but only one at
a time.
 Aspects of MHC (continued)
6. MHC polymorphism is determined only
in the germline.
7. Cytokines (especially interferon-γ)
increase level of expression of MHC.
 Aspects of MHC (continued)
8 Alleles for MHC genes are co-dominant.
Each MHC gene product is expressed on
the cell surface of an individual nucleated
cell.
• Why the high degree of polymorphism?

Survival of species!
 Accessory Molecules Involved
in Cell-Cell Interactions
T cell surface molecules that engage with ligand on
2nd cell when TCR recognizes MHC-peptide
T Cell Ligand on 2nd Cell
CD4 class II MHC (β2 domain)
CD8 class I MHC (α3 domain)
LFA-2 LFA-3
LFA-1 ICAM-1, ICA-2
LFA = Leukocyte Function-associated Antigen
ICAM = InterCellular Adhesion Molecule
Interactions of Th Cell and APC
T LFA-2 LFA-1 TCR CD28
helper
lympho
cyte

IL-1 TNF-beta
CD4
IL-6 pepti IFN-gamma
TNF-alpha de GM-CSF
IL-12 IL-4
IL-15

Antigen- LFA-3 ICAM-1Class II B7-1/B7-2

presenti MHC (CD80/CD86
ng
 Interactions of Tc Cell and Target Cell
T
LFA-1 TCR LFA-2
cytotoxi
c
lympho
cyte
CD8
pept
ide

Target ICAM-1 Class I LFA-3

cell MHC
Differential cell-type expression
of class I and class II molecules
correlates with the specialized
functions of different types of
immune cells
• MHC class I expression is widespread on
virtually every cell of the body. This is
consistent with the protective function of
cytotoxic TC lymphocytes which
continuously survey cell surfaces and kill
cells harboring metabolically active
microorganisms.
• MHC class II expression is restricted to
"antigen presenting cells." This is consistent
with the functions of helper TH lymphocytes
which are locally activated wherever these
cells encounter macrophages, dendritic
cells, or B cells that have internalized and
processed antigens produced by pathogenic
organisms.