1. M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.,Research scholar

2.  Genes in the MHC were first identified as
being important genes in rejection of
transplanted tissues
 Genes within the MHC were highly
polymorphic
 Studies with inbred strains of mice showed
that genes within the MHC were also involved
in controlling both humoral and cell-
mediated immune responses
 Responder/Non-responder strains

3.  There were three kinds of molecules encoded
by the MHC
 Class I
 Class II
 Class III
 Class I MHC molecules are found on all
nucleated cells (not RBCs)
 Class II MHC molecules are found on APC
 Dendritic cells, Macrophages, B cells, other cells

4. Class I MHC
Class II MHC
RBCs
APCs
Nucleated cells

5.  Class III MHC molecules
 Some complement components
 Transporter proteins

6.  It was not until the discovery of how theTCR
recognizes antigen that the role of MHC genes in
immune responses was understood
 TCR recognizes antigenic peptides in association with
MHC molecules
 T cells recognize portions of protein antigens that
are bound non-covalently to MHC gene products
 Tc cells recognize peptides bound to class I MHC
molecules
 Th cells recognize peptides bound to class II MHC
molecules

7.  Three dimensional structures of MHC
molecules and theTCR have been determined
by X-ray crystallography

8.  Two polypeptide
chains, a long α chain
and a short β (β2
microglobulin)
 Four regions
◦ Cytoplasmic region
containing sites for
phosporylation and
binding to cytoskeletal
elements
◦ Transmembrane region
containing hydrophobic
amino acids

9.  Four regions
 A highly conserved α3
domain to which CD8
binds
 A highly polymorphic
peptide binding region
formed from the α1 and
α2 domains
 Β2-microglobulin
helps stabilize the
conformation

10. Variability map of Class 1 MHC α Chain

11.  Groove composed of an α
helix on two opposite
walls and eight β-pleated
sheets forming the floor
 Residues lining the groove
are most polymorphic
 Groove accomodates
peptides of 8-10 amino
acids long
From Janeway et al., Immunobiology 6th Ed.

12.  Specific amino acids
on peptide required
for “anchor site” in
groove
 Many peptides can
bind
 Vaccine development
From Janeway et al., Immunobiology 6th Ed.

13. Locus
Number of alleles
(allotypes)
HLA - A 218
HLA - B 439
HLA - C 96
There are also HLA - E,
HLA - F and HLA - G
Relatively few alleles

14.  Two polypeptide
chains,α and β, of
roughly equal length
 Four regions
 Cytoplasmic region
containing sites for
phosporylation and
binding to cytoskeletal
elements

15.  Four regions
◦ Transmembrane region
containing hydrophobic
amino acids
◦ A highly conserved α2 and
a highly conserved β2
domains to which CD4
binds
◦ A highly polymorphic
peptide binding region
formed from the α1 and β1
domains

16. Variability map of Class2 MHC β Chain

17.  Groove composed of an
α helix on two opposite
walls and eight β-
pleated sheets forming
the floor
 Both the α1 and β1
domains make up the
groove
 Residues lining the
groove are most
polymorphic
From Janeway et al., Immunobiology 6th Ed.

18.  Groove is open and
accomodates
peptides of 13-25
amino acids
long, some of which
are ouside of the
groove
 Anchor site rules
apply
From Janeway et al., Immunobiology 6th Ed.

19. Locus
Number of alleles
(allotypes)
HLA - DPA
HLA - DPB
12
88
HLA - DQA
HLA - DQB
17
42
HLA - DRA
HLA - DRB1
HLA – DRB3
HLA – DRB4
HLA – DRB5
2
269
30
7
12
There are also HLA - DM and HLA - DO Relatively few alleles

20.  Although there is a high degree of
polymorphism for a species, an individual
has maximum of six different class I MHC
products and only slightly more class II MHC
products (considering only the major loci).
 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.

21.  Because each MHC molecule can bind many
different peptides, binding is termed
degenerate.
 MHC polymorphism is determined only in
the germline. There are no recombinational
mechanisms for generating diversity.
 MHC molecules are membrane-bound;
recognition byT cells requires cell-cell
contact.

22.  Alleles for MHC genes are co-dominant.
Each MHC gene product is expressed on the
cell surface of an individual nucleated cell.
 A peptide must associate with a given MHC
of that individual, otherwise no immune
response can occur. That is one level of
control.

23.  MatureT cells must have aT cell receptor
that recognizes the peptide associated with
MHC. This is the second level of control.
 Cytokines (especially interferon-γ) increase
level of expression of MHC.

24.  Peptides from the cytosol associate with
class I MHC and are recognized byTc cells .
Peptides from within vesicles associate with
class II MHC and are recognized byTh cells.
 Why so much polymorphism?
 Survival of the species

25.  Heterodimer with one α
and one β chain of
roughly equal length
 A short cytoplamic tail
not capable of
transducing an
activation signal
 A transmembrane
region with hydrophobic
amino acids

26.  Both α and β chains have
a variable (V) and
constant (C) region
 V regions of the α and β
chains contain
hypervariable regions that
determine the specificity
for antigen

27.  EachT cell bearsTCRs
of only one specificity
(allelic exclusion)

28.  Generation of a vast array of BCRs is
accomplished by recombination of variousV,
D and J gene segments encoded in the
germline
 Generation of a vast array ofTCRs is
accomplished by similar mechanisms
 TCR β chain genes haveV, D and J gene segments
 TCR α chain genes haveV and J gene segments

29. V-D rearrangement
D-J rearrangement
Transcription
Germline ß-Chain Gene
Vß1L
P
VßnVß2L
P
L
P
Dß1 Jß11--------Jß16 Dß2Cß1 Jß11---------------Jß17 Cß2
E
DNA
Vß1L
P
VßnVß2L
P
L
P
Dß1Jß15 Cß1 Dß2 Jß11---------------Jß17 Cß2
E
Vß1L
P
L
P
DNA
Vß2 Dß1Jß15 Cß1 Dß2 Jß11---------------Jß17 Cß2
E
RNA
Vß2 Dß1Jß15 Cß1

30. Property BCR (sIg) TCR
Genes
Many VDJs, Few Cs Yes Yes
VDJ rearrangement Yes Yes
V regions generate Ag-binding site Yes Yes
Allelic exclusion Yes Yes
Somatic mutation Yes No
Proteins
Transmembrane form Yes Yes
Secreted form Yes No
Isotypes with different functions Yes No
Valence 2 1

31.  Small population ofT cells express aTCR that
contain γ and δ chains instead of α and β
chains
 The Gamma/DeltaT cells predominate in the
mucosal epithelia and have a repertoire
biased toward certain bacterial and viral
antigens
 Genes for the δ chains haveV, D and J gene
segments; γ chains haveV and J gene
segments
 Repertoire is limited

32.  Gamma/DeltaT cells can recognize antigen in
an MHC-independent manner
 Gamma/DeltaT cells play a role in responses
to certain viral and bacerial pathogens

33.  TCR is closely
associated with a
group of 5 proteins
collectively called the
CD3 complex
◦ γ chain
◦ δ chain
◦ 2 ε chains
◦ 2 ξ chains
 CD3 proteins are
invariant

34.  CD3 complex
necessary for cell
surface expression of
TCR duringT cell
development
 CD3 complex
transduces signals to
the interior of the
cells following
interaction of Ag with
theTCR

35.  The interaction between
theTCR and MHC
molecules are not strong
 Accessory molecules
stabilize the interaction
◦ CD4/Class II MHC or
CD8/Class I MHC
◦ CD2/LFA-3
◦ LFA-1/ICAM-1

36.  Specificity for antigen
resides solely in theTCR
 The accessory
molecules are invariant
 Expression is increased
in response to cytokines

37.  Engagement ofTCR and
Ag/MHC is one signal needed
for activation ofT cells
 Second signal comes from
costimulatory molecules
◦ CD28 onT cells interacting with
B7-1 (CD80) or B7-2 (CD86)
◦ Others
 Costimulatory molecules are
invariant
 “Immunological synapse”

38.  Engagement ofTCR and
Ag/MHC in the absence of
costimulation can lead to
anergy
 Engagement of costimulatory
molecules in the absenece of
TCR engagement results in no
response
 Activation only occurs when
bothTCR and costimulatory
molecules are engaged with
their respective ligands
 Downregulation occurs if
CTLA-4 interacts with B7
◦ CTLA-4 send inhibitory signal

39.  APC must process and present peptides toT cells
 T cells must receive a costimulatory signal
 Usually from CD28/B7
 Accessory adhesion molecules help to stabilize binding ofT
cell and APC
 CD4/MHC-class II or CD8/MHC class I
 LFA-1/ICAM-1
 CD2/LFA-3
 Signal from cell surface is transmitted to nucleus
 Second messengers
 Cytokines produced to help drive cell division
 IL-2 and others