Immunology 7

Major Histocompatibility
Complex (MHC)
Structure, function and gene
organization
Dr.D.RATHNAMMA
Professor and Head
Dept. of Veterinary Microbiology, Veterinary
College, KVAFSU, Hebbal, Bengaluru-560 024
Major Histocompatibility Complex (MHC)
• MHC is a large genetic complex with multiple loci that
encode membrane bound (Class I and II) and non
membrane bound (Class III) glycoproteins called MHC
molecules.
• MHC molecules (Class I & II) are the antigen presenting
specialized receptor glycoproteins encoded in a gene
cluster called MHC in most of vertebrate animals.
• All vertebrates from fish to mammals possess MHC .
Each mammalian MHC contains approx. 200 expressed
genes, divided into 3 classes; MHC Class I, II, III
• Complete set of alleles found within an individual
animal’s MHC is called ‘MHC haplotype’
Significance of the MHC
• role in immune response
• role in organ transplantation
• role in predisposition to disease
• The MHC got its name from the fact that the
genes in this region encode proteins that
determine whether a tissue transplanted
between two individuals is ‘accepted’ as self
(histo compatible) or ‘rejected’ as foreign
(histo incompatible).
• MHC is located on Chromosome 6 in humans
and Chromosome 17 in Mice
• Size - 4000kb in humans, 1500 kb in Mice
Expression of MHC molecules
Structure of MHC Class I and II molecules
Structure of MHC Class I and II molecules
Collective name given to MHC molecules in
different species:
• Human - HLA, Human Leukocyte Antigens
• Bovines - BoLA, Bovine Leukocyte Antigens
• Dogs - DLA, Dog Leukocyte Antigens
• Sheep - OLA, Ovine Leukocyte Antigens
• Horses - ELA, Equine Leukocyte Antigens
• Swine - SLA, Swine Leukocyte Antigens
• Rabbit - RLA, Rabbit Leukocyte Antigens
• Chicken - B complex
• Mice - H-2 complex - first identified as
transplantation antigens (histocomatibility 2
genes)
Organization of MHC genes
• MHC class I genes classified into highly
polymorphic Classical class Ia genes and
less polymorphic non classical class Ib, Ic and
Id genes.
• ‘Polymorphism’ refers to structural variation
between molecules.
• MHC molecules differ from one individual to
other individuals because of presence of
multiple alleles.
Structure of MHC Class I molecule:
• Two polypeptide chains; a long α chain
and a short β chain called β2
microglobulin.
• The α chain is organized into three
external domains (α 1, α 2, and α 3),
each approximately 90 aa long ;
a trans membrane segment of about 25
hydrophobic aa followed by a short
stretch of charged (hydrophilic) aa; and
a cytoplasmic anchor segment of 30 aa.
• β2 microglobulin is a small chain
encoded by agene located on a
different chromosome, similar in size
and organization to the α3 domain.
• β2 microglobulin does not contain
trans membrane region and is
noncovalently bound to the α3
domain.
Class I MHC
Four regions of MHC class I :
1. Peptide(Ag) binding region:
a groove formed from α1 and
α2 domains of the α chain;
variable regions
2. Highly conserved α3 domain;
constant region, a site to which CD8+ on Tc cell binds.
3. Trans membrane segment: a stretch of hydrophobic
amino acids spanning plasma membrane
4. Cytoplasmic tail: contains sites for phosphorylation and
binding to cytoskeletal elements.
• Association of α chain with β2 microglobulin is
required for expression of complete MHC class I
molecule .
• All three molecules (MHC class I α chain, β2
microglobulin , and a peptide) are essential to the
proper folding and expression of the MHC-
peptide (antigen) complex on the cell surface.
• The peptide-binding groove is located on the top
surface of the class I MHC molecule, and it is
large enough to bind a peptide of 8 to 10 amino
acids.
Structure of MHC class II molecule:
• MHC class II molecule
contains two different
polypeptide chains, a 33-kDa
α chain and a 28-kDa β chain,
which associate by non
covalent interactions .
• MHC class II molecules are
membrane bound
glycoproteins that contain
external domains (α1, α2 ,
β1, β2), a trans membrane
segment, and a cytoplasmic
anchor segment.
Four regions of MHC class II :
1. Peptide binding region :
a groove formed by α1 and β1
domains of the α and β chains;
variable regions, site of polymorphism
The peptide-binding groove is large enough to bind a
peptide of 13 to 18 amino acids.
2. Highly conserved α 2 and β2 domains : constant
regions- β2 domain is the site to which CD4 on TH cell
binds.
3. Trans membrane segment: a stretch of hydrophobic
amino acids spanning plasma membrane
4. Cytoplasmic tail: contains sites for phosphorylation
and binding to cytoskeletal elements.
Antigen presenting cells (APCs)
Functions of class I and Class II MHC molecules:
• Class I MHC molecules are
involved in presentation of
intracellular or endogenous
antigens ( Viral antigens, tumour
antigens, intracellular bacterial/
fungal antigens ) to Tc cells (CD8+
T cells) resulting CMI response.
• Class II MHC molecules are
involved in presentation of
extracellular antigens or
exogenous antigens by APCs such
as Dendritic cells, Macrophages
and B lymphocytes to TH cells
(CD4+ T cells) resulting both
humoral (TH2 cells) and CMI (TH1
cells) response.
Antigen processing and presentation by MHC
molecules
Kuby Immunology
Interaction of APCs with T lymphocytes.
Antigen is presented as peptide MHC class-I/II complexes (signal 1).
T lymphocytes are activated by interacting with costimulatory molecules (signal 2).
Kuby Immunology
MHC Class III genes:
• MHC Class III region encodes several

molecules that are critical to immune function
but have little in common with class I or II
molecules.
• MHC Class III products include the
complement components C4, C2, and factor B,
as well as several inflammatory cytokines,
including the two tumor necrosis factor
proteins (TNF α and TNF β).
Avian MHC :
also referred as ‘B complex’
• The B complex is only 92 kb in length and contains only
19 genes , located on micro chromosome 16, Avian
MHC is fully sequenced.
• Chickens have two genetically distinct regions that
both contain MHC genes. B region, the locus
responsible for graft rejection, chickens have a second
region, Y region, also called Rfp-Y, that also contains
polymorphic class I genes.
• The class III region of chickens (represented in this case
by only a single gene, (C4) is located outside the class I
and II genes and not between them as is the case in
humans. In addition, the TAP genes (which are involved
in class I antigen presentation) are located in the
vicinity of class I genes in chickens, where as in the
class II region in mammals.
Avian MHC …….
Thickness of arrows pointing up indicates the level of expression; co evolution between the
TAP genes and the BF2 class I gene is indicated by a curved arrow beneath the genes. Red,
genes from class I system; blue, genes from class II system; green, genes from class III or
other regions. Solid colors indicate classical genes while striped colors indicate genes
involved in peptide loading.
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Major Histocompatibility

• MHC Class III region encodes several

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