Major Histocompatibility Complex (MHC)

4/9/2020Department of Life Science, SPU Balaghat1

MAJOR HISTOCOMPATIBILITY COMPLEX
STRUCTURE AND FUNCTION OF:-
•MHC CLASS I MOLECULE
•MHC CLASS II MOLECULE
•MHC CLASS III MOLECULE
DIFFERENCES BETWEEN MHC CLASS I AND II MOLECULES
H-2 COMPLEX OF MOUSE
MHC COMPLEX OF HUMAN
STRUCTURE OF TCR
ANTIGEN RECOGNITION BY T CELL
MHC I / TC CELL INTERACTION
MHC II / TH CELL INTRACTION
MHC RESTRICTION
ANTIGEN PROCESSING AND PRESENTATION PATHWAYS
• THE CYTOSOLIC PATHWAY
• THE ENDOCYTIC PATHWAY
FUNCTIONS OF MHC
4/9/2020
Department of Life Science, SPU Balaghat
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 MOLECULAR WEIGHT-45 KD.
 Class I MHC molecules is a membrane spanning molecule
,approximately 350 amino acids in length, 75 amino acids comprising the
transmembrane and cytoplasmic portions. The remaining 270 amino acids
are divided into three globular domains α-1,α-2 and α-3.
 The alpha chain is a transmembrane glycoprotein encoded by A,B, and C
regions of the human HLA complex and within the K and D regions of
mouse H-2 complex.
 The second portion of the molecule is a small globular protein called β-2
Microglobulin associates with the α-3 domain and is necessary for MHC
stability.β-2 Microglobulin is a protein encoded by highly conserved gene
located on different chromosomes.

 The β2 – microglobulin is non-covalently associated with the α3
domain.
 The α1 and α2 domains interact to form 8 antiparallel β strands
spanned by 2 long α–helical regions. This region is capable of binding
(via non-covalent interactions) a small peptide of about 10 amino
acids. This small peptide is "presented" to a T-cell and defines the
antigen "epitope" that the T-cell recognizes.
 The peptide-binding cleft is located on the top surface of the MHC
Class I molecule and it is large enough to bind a peptide of 8 to 10
amino acids.
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CLASS II MHC MOLECULE
Class II molecules are composed of two polypeptide chains
These polypeptides (alpha and beta) are about 230 and 240 amino
acids long, respectively, and are glycosylated, giving molecular weights
of about 33 kDa and 28 kDa.
These polypeptides fold into two separate domains; alpha-1 and
alpha-2 for the alpha polypeptide, and beta-1 and beta-2 for the beta
polypeptide.
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Between the alpha-1 and beta-1 domains
lies a region very similar to that seen on
the class I molecule. This region, bounded
by a beta-pleated sheet on the bottom and
two alpha helices on the sides, is capable
of binding (via non-covalent interactions) a
small peptide of about 10 amino acids.
This small peptide is "presented" to a T-cell
and defines the antigen "epitope" that the
T-cell recognizes.
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These are heterogenous molecules .
Include complement component C2, C4 and factor
B(components responsible for formation of C3 convertase).
They also include heat shock proteins and tumour
necrosis factor.
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MHC class I MHC class II
Comprised of an MHC-encoded a chain
and a b2-microglobulin chain
Comprised of MHC-encoded a and b
chains
Present on most cells Present only on antigen-presenting cells
Bind endogenous antigens synthesized in
a cell
Binds exogenous antigens
Present antigen to cytotoxic T cell
lymphocytes
Present antigen to helper T cell
lymphocytes
Bind CD8 adhesion molecules on
cytotoxic T cells
Bind CD4 adhesion molecules on helper
T cells
Presence of foreign or over-abundant
antigens targets cell for destruction
Presence of foreign antigens induces
antibody production, and attracts immune
cells to area of infection
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The mouse MHC is located on chromosome 17.
Class I MHC:
• It consists of two major loci, K and D.
•These 2 loci are not together but they are separated by class II and class III genes.
Class II MHC:
•The class II gene complex contains two loci, A and E each of which code for
one α- and one ß- chain polypeptide, which form one class II molecule.
•The mouse class II gene complex is also known as the I-region and the genes
in this complex are referred to as Ir (immune response) genes .
•Products of A and E loci are also termed IA and IE antigens, collectively known
as Ia antigens.
4/9/2020
Department of Life Science, SPU Balaghat12

The human MHC is located on chromosome 6.
Class I MHC:
•The class I gene complex contains three major loci as B, C and A .
• Each these loci codes for a polypeptide, α-chain.
•Each α-chain associates with a β-2 microglobulin molecule , This α-β-chain complex is
expressed on the cell surface.
Class II MHC:
•The class II gene complex contains three loci, DP, DQ and DR; each of these loci codes
for one α- and a variable number of ß-chain polypeptides which associate together to
form the class II antigens.
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It’s a hetrodimer.
2 polypeptide chains are present(α and β)
Divided into constant and variable arm.
3 hypervarible regions are present in variable
arm for antigen recognition.
Assessory molecule called CD3 then
transmits the signal.
T-cells activation
Release of lymphokines.
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 The TCR provides the specificity for an
individual T-cell to recognize its particular
antigen. However, this recognition is
"MHC-restricted" because the TCR also
requires interactions with MHC.
 Interactions between the CD4 molecule
(found on helper T-cells) and class II MHC
or the CD8 molecule (found on cytotoxic T-
cells) and class I MHC stabilize and
consummate the antigen recognition
process, allowing helper T-cells to respond
to "exogenous" antigens (leading to B-cell
activation and the production of antibody)
or cytotoxic T-cells to respond to
"endogenous" antigens (leading to target
cell destruction). 4/9/2020
Department of Life Science, SPU Balaghat16

Most Tc cells (CD8+ Cells) possess both T-Cell Receptors (TCR) and
CD8+ molecules on their surfaces.
These TCRs are able to recognize peptides,only when they are expressed
in complexes with MHC I molecules.
Due to Genetic recombination events, each T-Cell expresses a unique
TCR, which will only bind a specific MHC-Peptide complex.
T-Cells that recognize self-peptides are released in the Thymus.
Any cell which is hosting a Virus or manufacturing mutant proteins (as in the
case of Cancer) will present these foreign Peptides upon its surface. A CD8+
Cell will recognize them and eventually the cell will be destroyed.
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The Helper T-Cells is responsible for regulating almost every Acquired Immune
System activity.
Helper T-Cells interact with MHC II-Peptide complex, in order to be activated.
Instead of CD8 molecule Helper T-Cells, have a molecule called CD4, which binds to
MHC II.
As in the case of CD8+ Cells, self-reactive cells are destroyed in the Thymus, so if a
Peptide is recognized, it is probably of foreign origin.
Assuming the APC which presented the MHC II-Peptide complex produce cytokines
to allow its own maturation and propagation.
These CD4+ Cells will then proceed to supply the necessary cytokines for Immune
Responses against antigen they recognize.
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MHC restriction is the recognition of foreign antigen located on the
surface of cells. Cytotoxic T lymphocytes usually respond to foreign
antigen in association with Class I MHC antigen whereas T helper cells
responds to foreign antigen in association with Class II MHC antigens.
The presentation of antigens by macrophages to T cells appear
to be very specific. The macrophages that present antigen to TH cells
should have Class II MHC antigens on their surface whereas
macrophages that present antigen to Tc cells should have Class I MHC
antigens. When the macrophage bears a different MHC antigen, it cannot
cooperate and thus antigen presentation cannot occur, this is called as
MHC restriction.
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The intracellular and extracellular antigens are eliminated by
different pathways in immune system. There are basically two pathways for their
eliminations:-
THE CYTOSOLIC PATHWAY:-
Generally endogenous antigens are processed in the cytosolic
pathway and presented on the membrane with class I MHC molecules
THE ENDOCYTIC PATHWAY:-
Exogenous antigens are processed in the endocytic pathway
and presented on the membrane with class II MHC molecule
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Endogenous antigen are degraded by proteosomes.
Peptide is transported to RER via TAP.
Class I MHC α chain binds calnexin,then β-2
microglobulin.calreticulam,tapasin and ERP57 bind. MHC capture
peptides and chaperones dissociates.
Class I MHC-peptide is transported from RER to Golgi complex to
plasma membrane.
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 Class II MHC α and β binds invariant chain blocking binding of endogenous
antigen.
 MHC complex is routed through Golgi to endocytic pathway compartments.
 Invariant chain is degraded,leaving CLIP fragment.
 Exogenous antigen is taken up,degraded, routed to endocytic pathway
compartments.
 HLA-DM mediates exchange of CLIP for antigenic peptide.
 Class II MHC-peptide is then transported to plasma membrane.
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 Production of Human Leucocyte Antigen
Production of Immune Associated Antigens
Controls the levels of the Complement Components
HLA Complex help In T-cell recognition
Graft Rejection
Non-immunological function of MHC
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KUBY IMMUNOLOGY- BY OSBARNE,GOLDSBY AND
KINDT
IMMUNOLOGY- BY ROITT
IMMUNOLOGY-BY VED PATHAK
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Major Histocompatibility Complex (MHC)

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