MHC lecture.pptx

Major Histocompatibility Complex
(MHC)
BY: DR SADAF MOEEZ

Major Histocompatibility Complex (MHC)

The process by which T
cells are screened so that
only those capable of
binding to MHC are kept
alive called positive
selection
A T cell recognizes antigen as a
peptide bound by a particular
allelic variant of an MHC
molecule, and will not recognize
the same peptide bound to other
MHC molecules. This behavior of T
cells is called MHC restriction
The outstanding feature of
the MHC molecules is their
extensive polymorphism
At least three properties of MHC
molecules are affected by MHC
polymorphism: the range of
peptides bound; the conformation
of the bound peptide; and the
direct interaction of the MHC
molecule with the T-cell receptor
The interaction between
TCRs and peptide-MHC
complex is significant in
maintaining the immune
system against foreign
antigens

Structure of Class II Molecule

Difference between MHC I and MHC II

1. Antigen Processing
Before an antigen can be presented, it must first be processed.
Processing transforms proteins into antigenic peptides.
 MHC Class I Molecules
1. Intracellular peptides for MHC class I presentation are made
by proteases and the proteasome in the cytosol.
2. Then transported into the endoplasmic reticulum via TAP
(Transporter associated with Antigen Processing) to be further
processed.
3. They are then assembled together with MHC I molecules and
travel to the cell surface ready for presentation.
Antigen Processing and Presentation

 MCH Class II Molecules
1. The route of processing for exogenous antigens for MHC class
II presentation begins with endocytosis of the antigen.
2. Once inside the cell, they are enclosed within endosomes that
activate proteases, to degrade the antigen.
3. MHC class II molecules are transported into endocytic
vesicles where they bind peptide antigen, and then travel to the
cell surface.

General process of antigen processing and presentation

2. Antigen Presentation
 The antigen presented on MHCs is recognised by T
cells using a T cell receptor (TCR). These
are antigen-specific.
 Co-receptors
 As well as the TCR, another T cell molecule is required
for antigen recognition and is known as a co-receptor.
These are either a CD4 or CD8 molecule:
 CD4 is present on T helper cells and only binds to
antigen-MHC II complexes.
 CD8 is present on cytotoxic T cells and only binds to
antigen-MHC I complexes.

 This therefore leads to very different effects.
1. Antigens presented with MHC II will activate T helper cell.
2. Antigens presented with MHC I activate cytotoxic T cells.
 Cytotoxic T cells will kill the cells that they recognise, whereas T
helper cells have a broader range of effects on the presenting cell such
as:
1. Activation to produce antibodies (in the case of B cells)
2. Activation of macrophages to kill their intracellular pathogens.

Antigen Presentation
Antigens are delivered to the surface of APCs by Major
Histocompatibility Complex (MHC) molecules.
Different MHC molecules can bind different peptides. The MHC
is highly polygenic and polymorphic which equips us to
recognise a vast array of different antigens we might
encounter.
There are different classes of MHC, which have different
functions:
MHC class I molecules are found on all nucleated cells (not just
professional APCs) and typically present intracellular antigens
such as viruses.
MHC class II molecules are only found on APCs and typically
present extracellular antigens such as bacteria.

Endogenous Antigens
• Endogenous antigens are proteins found within the
cytosol of human cells. Examples of endogenous
antigens include:
1. Viral proteins produced during viral replication.
2. Proteins produced by intracellular bacteria such as
Rickettsias during their replication.
3. Proteins that have escaped into the cytosol from the
phagosome of phagocytes such as antigen-presenting
cells.
4. Tumor antigens produced by cancer cells.
5. Self-peptides from host cellular proteins.
Endogenous Antigens

ENDOGENOUS PATHWAY
• Endogenous antigens pass through proteasomes where they are
degraded into a series of peptides.
• The peptides are transported into the rough endoplasmic reticulum
(ER) by a transporter protein called TAP.
• The peptides then bind to the grooves of newly synthesized MHC-I
molecules.
• The endoplasmic reticulum transports the MHC-I molecules with
bound peptides to the Golgi complex.
• The Golgi complex, in turn, transports the MHC-I/peptide
complexes by way of an exocytic vesicle to the cytoplasmic
membrane where they become anchored.
• Here, the peptide and MHC-I/peptide complexes can be recognized
by by a complementary-shaped T-cell receptor (TCR) and a CD8
molecule, a co-receptor, on the surface of either a naive T8-
lymphocyte or a cytotoxic T-lymphocyte (CTL).
Endogenous Pathway

Factors required for Endogenous
Pathway
• Proteasomes are complex intracellular proteases that function
in regulated degradation of cellular proteins.
• Calreticulin and calnexin: Type of molecular chaperone
proteins, involved in the assembly of MHC-I and in the
processing of intracellular peptides.
• Transporter associated with antigen processing (TAP):
protein complex belongs to the ATP-binding-cassette
transporter family. essential for peptide delivery from the
cytosol into the lumen of the endoplasmic reticulum (ER),
where these peptides are loaded on major histocompatibility
complex (MHC) I molecules.
• TAP-associated glycoprotein or Tapasin is a critical cofactor.
It promotes the assembly of major histocompatibility complex
(MHC) class I molecules with peptides.
Factors required for Endogenous Pathway

A Cytotoxic T-lymphocyte Recognizing a Virus-Infected Cell. Endogenous
antigens are those being produced within the cytosol of the cells of the body.
Examples include proteins from replicating viruses, proteins from intracellular
bacteria, and tumor antigens. The body marks infected cells and tumor cells
for destruction by placing peptide epitopes from these endogenous antigens
on their surface by way of MHC-I molecules. Cytotoxic T-lymphocytes (CTLs)
are then able to recognize peptide/MHC-I complexes by means of their T-cell
receptors (TCRs) and CD8 molecules and kill the cells to which they bind.

EXOGENOUS PATHWAY
 Exogenous antigens, such as viruses, are engulfed and placed in a
phagosome.
 Lysosomes fuse with the phagosome forming an phagolysosome.
 Protein antigens are degraded into a series of peptides.
 MHC-II molecules are synthesized in the endoplasmic reticulum. Within
the endoplasmic reticulum, a protein called the invarient chain (Ii)
attaches to the the peptide-binding groove of the MHC-II molecules and in
this way prevents peptides designated for binding to MHC-I molecules
within the ER from attaching to the MHC-II.
 As the MHC-II molecules with bound Ii chain are transported to the Golgi
complex, the Ii is cleaved, leaving a short peptide called CLIP in the
groove of the MHC molecule.
 The vesicles containing the MHC-II molecules fuse with the peptide-
containing phaglysosomes.
Exogenous Pathway

The CLIP peptide is removed from the MHC-II
molecules and the peptide epitopes are now free
to bind to the grooves of the MHC-II molecules.
The MHC-II molecules with bound peptides are
transported to the cytoplasmic membrane where
they become anchored.
Here, the peptide and MHC-II complexes can be
recognized by T4-lymphocytes by way of TCRs
and CD4 molecules having a complementary
shape.
Exogenous Pathway

MHC-II molecules with
bound peptides can be
recognized by a
complementary-shaped T-cell
receptor and a CD4 molecule,
a co-receptor, on the surface of
a T4-lymphocyte
T4-lymphocytes are the cells
the body uses to regulate both
humoral immunity and cell-
mediated immunity.

• The invariant chain (Abbreviated Ii) is a
polypeptide which plays a critical role in
antigen presentation. It is involved in the
formation and transport of MHC class II
peptide complexes for the generation of CD4+
T cell responses.
• Class II-associated invariant chain peptide
(CLIP): When Ii undergoes degradation and
leave a peptide fragment (85–101) in length.

MHC lecture.pptx

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MHC lecture.pptx