Immunology Lecture MHC

THE MAJOR
HISTOCOMPATIBILITY COMPLEX
In all vertebrates there is a genetic region that has a

major influence on immune responses. This region is
referred to as the Major Histocompatibility Complex
(MHC).
In humans, MHC region has a size of 3.6-Mb and is

located on chromosome 6 having 140 genes.
About half of these genes have known immune functions.
1
Subgroups
The MHC region is divided into two main subgroups,

class I, and class II.
1. MHC class I: Present on all nucleated cells. They

present antigen fragments to cytotoxic T cells via
the CD8 receptor on these cells and also bind
inhibitory receptors on Natural Killer (NK) cells.
2. MHC class II: Present on most immune system

cells, specifically on APC. they present antigen
fragments to T-helper cells by binding to the CD4
receptor on the T-helper cells.
2
Structure of MHC proteins
The Class I and II molecules have a similar

secondary and tertiary structure with subtle
functional differences.
3
Class I and Class II molecules
These are membrane bound glycoproteins that form

highly stable complexes with antigen.
Class I: 45 kDa α chain (heavy) associated

noncovalently with 12 kDa β2-microglobulin
molecule (light chain)
Class II: 33 kDa α chain associated noncovalently

with a 30 kDa β chain
4
5
Class I MHC
α chain
Transmembrane glycoprotein
3 external domains (α 1, α 2, α 3)
α 1, α 2 form the peptide-binding cleft
α 3 is highly conserved and can interact with CD8

on Tc cells
6
7
Class II MHC
α and β chains
Transmembrane glycoprotein
4 external domains (α 1, α 2, β 1 and β 2)
Two transmembrane segments
8
Both classes of MHC molecule fold up to produce very
similar 3-D structures.
Each has 2 MHC-unique domains which fold together to

form a peptide binding platform whose base is formed
by a ß-pleated sheet structure.
This structure forms a cleft or groove which

accommodates a peptide.
The main difference between the 2 classes is the

dimensions of the peptide-binding groove which
accommodates 8-9 amino acids in class I but is open-
ended for class II.
9
10
11
Cell Type MHC I MHC II
Varies,
T cells +++ inducible in
some species
B cells +++ ++
Macrophages +++ +
Dendritic
+++ x10 +++ x10
cells
Granulocytes ++ -
Endothelium ++ - (inducible)
Hepatocytes + -
12
Allelic Polymorphism
The MHC is highly polymorphic. There are a large

number of alleles at each genetic locus.
Crucially many of these alleles are represented at

significant frequency (> 1%) in the population.
13
Allelic Polymorphism
In addition, the alleles generally differ from one another

by many (up to 30) amino acid substitutions.
For example in humans there are more than 200 alleles

described at some MHC loci.
Such a remarkable degree of polymorphism implies a

selective pressure to establish and maintain it.
14
MHC Loci
In man and mouse, as in most species, each class of

MHC is represented by more than one locus (polygeny).
In man these are called HLA (Human Leucocyte Antigen)
system.
The Class I loci are HLA-A, -B and -C and the Class II loci
are HLA-DR, -DQ and -DP.
15
16
All MHC loci are expressed co-dominantly (both the set
of alleles inherited from one's father and the set
inherited from one's mother are expressed on each cell).
The set of linked MHC alleles found on the same

chromosome is called a haplotype.
17
Biological role of the MHC
The products of the MHC play a fundamental role in

regulating immune responses.
T cells must recognize antigen as a complex with MHC

molecules.
This requires antigen to be processed by unfolding and

proteolytic digestion before it complexes with the MHC
molecule.
Once formed the complex of antigenic peptide and MHC

are generally very stable (half life ~ 24hrs).
18
Two pathways for antigen processing
The 2 classes of MHC molecule are specialized to present

different sources of antigen.
MHC class I molecules present endogenously

synthesized antigens, e.g. viral proteins.
MHC class II molecules present exogenously derived

proteins, e.g. bacterial products or viral capsid proteins.
19
MHC class I molecules are very unstable in the absence of
peptide.
They bind peptides in the endoplasmic reticulum (ER).
Peptides are generated continuously in the cytoplasm by

the degradation of proteins, predominantly by the
proteasome.
Peptides of suitable length (~8-18 amino acids) are

specifically transported across the ER membrane by a
transporter made up of the TAP1 and TAP2 molecules
(ATP binding transporters).
20
These peptides bind to the class I MHC molecules in the
ER if they have appropriate sequence motifs, the MHC
molecules being stabilized in a partially folded state by a
chaperone protein (calnexin).
The peptide bound class I MHC molecules adopt their

fully folded conformation, release calnexin and transit to
the cell surface via the Golgi apparatus.
21
MHC class II molecules bind to a third polypeptide in the
ER called invariant chain or Ii. It is necessary for
association of α and β proteins.
The invariant chain serves two other purposes. It controls

the binding of peptides to the Class II molecule and it
targets the class II molecule to a specialized endosomal
compartment (MIIC).
22
Exogenous antigens enter the cell in membrane
vesicles, either by fluid phase pinocytosis or receptor
mediated endocytosis.
These vesicles fuse with the MIIC compartment.
The MIIC compartment has an acid pH and contains

proteases.
23
This combination unfolds and degrades both the antigen
and the invariant chain causing the generation of
antigenic peptides and the release of Class II molecules
to bind those peptides with appropriate sequence motifs.
The Class II molecules, peptide complexed or "empty",

then traffic to the plasma membrane.
24

Immunology Lecture MHC

Uploaded by

Copyright:

Available Formats

Immunology Lecture MHC

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Immunology Lecture MHC

Uploaded by

Copyright:

Available Formats

THE MAJOR

In all vertebrates there is a genetic region that has a

In humans, MHC region has a size of 3.6-Mb and is

About half of these genes have known immune functions.

The MHC region is divided into two main subgroups,

1. MHC class I: Present on all nucleated cells. They

2. MHC class II: Present on most immune system

The Class I and II molecules have a similar

These are membrane bound glycoproteins that form

Class I: 45 kDa α chain (heavy) associated

Class II: 33 kDa α chain associated noncovalently

α 1, α 2 form the peptide-binding cleft

α 3 is highly conserved and can interact with CD8

4 external domains (α 1, α 2, β 1 and β 2)

Two transmembrane segments

Each has 2 MHC-unique domains which fold together to

This structure forms a cleft or groove which

The main difference between the 2 classes is the

The MHC is highly polymorphic. There are a large

Crucially many of these alleles are represented at

In addition, the alleles generally differ from one another

For example in humans there are more than 200 alleles

Such a remarkable degree of polymorphism implies a

In man and mouse, as in most species, each class of

The set of linked MHC alleles found on the same

The products of the MHC play a fundamental role in

T cells must recognize antigen as a complex with MHC

This requires antigen to be processed by unfolding and

Once formed the complex of antigenic peptide and MHC

The 2 classes of MHC molecule are specialized to present

MHC class I molecules present endogenously

MHC class II molecules present exogenously derived

They bind peptides in the endoplasmic reticulum (ER).

Peptides are generated continuously in the cytoplasm by

Peptides of suitable length (~8-18 amino acids) are

The peptide bound class I MHC molecules adopt their

The invariant chain serves two other purposes. It controls

These vesicles fuse with the MIIC compartment.

The MIIC compartment has an acid pH and contains

The Class II molecules, peptide complexed or "empty",

You might also like