UNIVERSITY OF BAMENDA

FACULTY OF HEALTH SCIENCES

DEPARTMENT OF MEDICAL LABORATORY SCIENCE

Part Lecture notes on Clinical Immunology MLS 3 (Dr Bisong Ebai)

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)

Learning objectives

 State which body cells display MHC-I surface molecules and which cells normally
display MHC-II surface molecules.
 Define endogenous antigen and exogenous antigen and state which class of MHC
molecule primarily binds each.
 State which type of T-lymphocyte recognizes epitopes from protein antigens on MHC-I
molecules and which type recognizes epitopes from protein antigens on MHC-II
molecules.
 State the role of proteasomes in binding of peptides from endogenous antigens by MHC-I
molecules.
 State the role of lysosomes in binding of peptides from exogenous antigens by MHC-II
molecules.
The Roles of MHC molecules in adaptive immune responses

MHC molecules are glycoproteins that enable T-lymphocytes to recognize epitopes of antigens
and discriminate self from non-self. Unlike B-cell receptors on B-lymphocytes that are able to
directly bind epitopes on antigens, the T-cell receptors (TCRs) of T-lymphocytes can only
recognize epitopes after they are bound to MHC molecules.

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Figure: Epitope-Specific Receptors on the Surface of B- and T-Lymphocytes. B-lymphocytes have B-cell
receptors that recognize epitopes directly on antigens. T-lymphocytes have TCR molecules that recognize epitopes
only after they have been placed on cells of the body by way of MHC molecules.

The MHC genes are the most polymorphic genes in the human genome, possessing many alleles
for each gene. The MHC genes are co-dominantly expressed so that an individual expresses the
alleles inherited from each parent. In this way, the number of MHC molecules that bind peptide
for presentation to T-lymphocytes is maximized. In addition, each MHC molecule is able to bind
a wide variety of different peptides, both self-peptides and foreign peptides. There are two
classes of MHC molecules: MHC-I and MHC-II.

 MHC-I molecules present epitopes to T8-lymphocytes.

 MHC-II molecules presents epitopes to T4-lymphocytes.

The expression of MHC molecules is increased by cytokines produced during both innate and
adaptive immune responses. Cytokines such as interferon-alpha, interferon-beta, interferon-
gamma, tumor necrosis factor increase the expression of MHC-I molecules, while interferon-
gamma is the main cytokine that increases the expression of MHC-II molecules.

MHC-I molecules

MHC-I molecules are designed to enable the body to recognize infected cells and tumor cells and
destroy them with cytotoxic T-lymphocytes (CTLs). CTLs are effector defense cells derived
from naive T8-lymphocytes. MHC-I molecules are:

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  Produced by all nucleated cells in the body.
 Possess a deep groove that can bind peptide epitopes, 8-11 amino acids long, typically
from endogenous antigens.
 Present MHC-I/peptide complexes to naive T8-lymphocytes and cytotoxic T-
lymphocytes possessing a complementary-shaped T-cell receptor or TCR.
 Through the process of cross-presentation, some antigen-presenting dendritic cells can
cross-present epitopes of exogenous antigens to MHC-I molecules for eventual
presentation to naive T8-lymphocytes.

Endogenous antigens are proteins found within the cytosol of human cells. Examples of
endogenous antigens include:

a. Viral proteins produced during viral replication;

b. Proteins produced by intracellular bacteria such as Rickettsias and Chlamydias during their
replication;
c. Proteins that have escaped into the cytosol from the phagosome of phagocytes such as antigen-
presenting cells;
d. Tumor antigens produced by cancer cells; and
e. Self-peptides from host cellular proteins.

During the replication of viruses and intracellular bacteria within their host cell, as well as during
the replication of tumor cells, viral, bacterial, or tumor proteins are degraded into a variety of
peptide epitopes by cylindrical organelles called proteasomes. The body's own cytosolic proteins
are also degraded into peptides by proteasomes.

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Figure: MHC Molecule with Bound Peptide Binding to a Complementary T-Cell Receptor. This illustration
shows a T-cell receptor (TCR) on the surface of a T-lymphocyte recognizing two polymorphic residues of a MHC
molecule and one residue of its bound peptide epitope.

These peptide epitopes are then attached to a groove of MHC-I molecules that are then
transported to the surface of that cell where they can be recognized 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). The TCRs recognize both the foreign peptide
antigen and the MHC molecule. TCRs, however, will not recognize self-peptides bound to
MHC-I. As a result, normal cells are not attacked and killed.

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Figure: Binding of Peptide Epitopes from Endogenous Antigens to MHC-I Molecules by a Dendritic Cell..

Dendritic cells bind epitopes from endogenous antigens to MHC-I molecules and present them to
naive T8-lymphocytes in order to activate these naive T8-lymphocytes.

1. Antigens are engulfed by dendritic cells and placed in a phagosome. Some of the proteins
escape from the phagosome into the cytosol of the dendritic cell where they become
endogenous antigens.
2. These endogenous antigens pass through proteasomes where they are degraded into a
series of peptides.
3. The peptides are transported into the rough endoplasmic reticulum (ER) by a transporter
protein called TAP.
4. The peptides then bind to the grooves of newly synthesized MHC-I molecules.
5. The endoplasmic reticulum transports the MHC-I molecules with bound peptides to the
Golgi complex.
6. 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 naive T8-lymphocytes by
way of TCRs and CD8 molecules having a complementary shape.

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Through the process of cross-presentation, some antigen-presenting dendritic cells can cross-
present epitopes of exogenous antigens to MHC-I molecules for eventual presentation to naive
T8-lymphocytes.

MHC-I molecule with bound peptide on the surface of antigen-presenting dendritic cells can be
recognized by a complementary-shaped TCR/CD8 on the surface of a naive T8-lymphocyte to
initiate cell-mediated immunity. Certain dendritic cells, as discussed later, can also cross-present
exogenous antigens to MHC-I molecules.

Figure: An Antigen-Presenting Dendritic Cell Presenting MHC-I with Bound Peptide to a Naive T8-lymphocyte
having a Complementary T-Cell Receptor.

Antigen-presenting dendritic cells produce both MHC-I and MHC-II molecules. These APCs can
phagocytose infected cells and tumor cells, place them in phagosomes, and degrade them with
lysosomes. During this process, some of the proteins escape from the phagosome into the
surrounding cytosol. Here they can be degraded into peptides by proteasomes, bound to MHC-I
molecules, and placed on the surface of the dendritic cell. Now the peptide/MHC-I complexes
can be recognized by a naive T8-lymphocyte having a complementary shaped T-cell receptor
(TCR) and CD8 molecule. This activates the naive T8-lymphocyte enabling it to eventually
proliferate and differentiate into cytotoxic T-lymphocytes (CTLs).

MHC-I molecule with bound peptide on the surface of infected cells and tumor cells can be
recognized by a complementary-shaped TCR/CD8 on the surface of a cytotoxic T-lymphocyte to
initiate destruction of the cell containing the endogenous antigen.

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Figure: Binding of Peptide Epitopes from Endogenous Antigens to MHC-I Molecules by a
Virus-Infected Cell. 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.

1. During viral replication within the host cell, endogenous antigens, such as viral proteins,
pass through proteasomes where they are degraded into a series of peptides. The process
continues as in other endogenous antigens described above.

MHC-I molecules are coded for by three MHC-I genes, HLA-A, HLA-B, and HLA-C. As
mentioned above, however, there are many different alleles for each gene that a person inherits.
In this way, the number of MHC-I molecules that bind peptides for presentation to T-8
lymphocytes is maximized. The expression of MHC-I molecules on all cell types is increased by
the cytokines interferon-alpha (IFN-a) and interferon-beta (IFN-ß).

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Figure: A Cytotoxic T-lymphocyte recognizing a Virus-Infected Cell.

MHC-II molecules

MHC-II molecules are designed to enable T4-lymphocytes to recognize epitopes of exogenous

antigens and discriminate self from non-self. MHC-II molecules are:

 Made by antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B-

lymphocytes.
 Possess a deep groove that can bind peptide epitopes, often 10-30 amino acids long but
with an optimum length of 12-16 amino acids, typically from exogenous antigens. The
peptides interact along their entire length with the groove.
 Present MHC-II/peptide complexes to naive T4-lymphocytes or effector T4-lymphocytes
that have a complementary shaped T-cell receptor or TCR.
 Through the process of cross-presentation, some antigen-presenting dendritic cells can
cross-present epitopes of endogenous antigens to MHC-II molecules for eventual
presentation to naive T4-lymphocytes.

Exogenous antigens are antigens that enter from outside the body, such as bacteria, fungi,
protozoa, and free viruses. These exogenous antigens enter macrophages, dendritic cells, and B-
lymphocytes through phagocytosis. The microbes are engulfed and placed in a phagosome which
then fuses with lysosomes. Following this fusion, the phagolysosome becomes acidified.

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Acidification, in turn, activates the proteases within the phagolysosome enabling protein antigens
from the microbe to be degraded into a series of short peptides. These peptide epitopes are then
attached to MHC-II molecules and are then transported to the surface of the antigen-presenting
cell (APC).

Figure: Binding of Peptide Epitopes from Exogenous Antigens to MHC-II Molecules

T4-lymphocytes are then able to recognize peptide/MHC-II complexes by means of their T-cell
receptors (TCRs) and CD4 molecules. 1. Exogenous antigens, such as viruses, are engulfed and
placed in a phagosome.2. Lysosomes fuse with the phagosome forming a phagolysosome. 3.
Protein antigens are degraded into a series of peptides. 4. MHC-II molecules are synthesized in
the endoplasmic reticulum and transported to the Golgi complex. Once assembled, within the
endoplasmic reticulum, a protein called the invarient chain (Ii) attaches to 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. 5. 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. 6&7. The vesicles containing the
MHC-II molecules fuse with the peptide-containing phaglysosomes. The CLIP peptide is

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removed from the MHC=II molecules and the peptide epitopes are now free to bind to the
grooves of the MHC-II molecules. 8. 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.
Some pathogens, such as Mycobacterium tuberculosis, Mycobacterium leprae, and Leishmania,
are able to grow in the endocytic vesicles of macrophages without being killed by lysosomes.
These macrophages can, however, become activated by T4-effector lymphocytes called TH1 cells
and subsequently use intravesicular proteases to degrade the proteins from these pathogens into
peptides for presentation to MHC-II molecules that pass through on their way to the cell surface.

Here the 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.

Figure: A T4-Lymphocyte Recognizing Epitope/MHC-II on an Antigen-Presenting Dendritic Cell.

MHC-II molecules are coded for by three MHC-II genes, HLA-DR, HLA-DP, and HLA-DQ.
Interferon-gamma (IFN- ?) increases the expression of both MHC-I and MHC-II molecules.

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Only antigen-presenting cells such as dendritic cells, macrophages, and B-lymphocytes produce
MHC-II molecules. Peptide epitopes bound to MHC-II molecules are recognized by TCRs and
CD4 molecules on the surfaces of naive T4-lymphocytes and on effector T4-lymphocytes.

Summary

1. MHC molecules enable T-lymphocytes to recognize epitopes and discriminate self from
non-self.
2. T-cell receptors (TCRs) of T-lymphocytes can only recognize epitopes - typically short
chains of amino acids called peptides - after they are bound to MHC molecules.
3. MHC-I presents epitopes to T8-lymphocytes; MHC-II presents epitopes to T4-
lymphocytes.
4. MHC-I molecules are designed to enable the body to recognize infected cells and tumor
cells and destroy them with cytotoxic T-lymphocytes or CTLs. (CTLs are effector
defense cells derived from naïve T8-lymphocytes.)
5. MHC-I molecules are made by all nucleated cells in the body; bind peptide epitopes
typically from endogenous antigens; present MHC-I/peptide complexes to naive T8-
lymphocytes and cytotoxic T-lymphocytes possessing a complementary-shaped T-cell
receptor or TCR.
6. Through the process of cross-presentation, some antigen-presenting dendritic cells can
cross-present epitopes of exogenous antigens to MHC-I molecules for eventual
presentation to naive T8-lymphocytes.
7. Endogenous antigens are proteins found within the cytosol of human cells and include
viral proteins produced during viral replication, proteins produced by intracellular
bacteria, proteins that have escaped into the cytosol from the phagosome of phagocytes
such as antigen-presenting cells, and tumor antigens produced by cancer cells.
8. During the replication of viruses and intracellular bacteria within their host cell, as well
as during the replication of tumor cells, viral, bacterial, or tumor proteins are degraded
into a variety of peptide epitopes by cylindrical organelles called proteasomes. The
resulting peptide epitopes are then attached to MHC-I molecules that are then transported
to the surface of that cell.

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9. Exogenous antigens are antigens that enter from outside the body such as bacteria, fungi,
protozoa, and free viruses.
10. MHC-II molecules are made by antigen-presenting cells or APCs, such as dendritic cells,
macrophages, and B-lymphocytes; bind peptide epitopes typically from exogenous
antigens; and present MHC-II/peptide complexes to naive T4-lymphocytes or effector
T4-lymphocytes that have a complementary shaped T-cell receptor or TCR.
11. Through the process of cross-presentation, some antigen-presenting dendritic cells can
cross-present epitopes of endogenous antigens to MHC-II molecules for eventual
presentation to naive T4-lymphocytes.
12. Exogenous antigens enter antigen-presenting macrophages, dendritic cells, and B-
lymphocytes through phagocytosis, and are engulfed and placed in a phagosome where
protein antigens from the microbe are degraded by proteases into a series of peptides.
These peptides are then attached to MHC-II molecules that are then put on the surface of
the APC.

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