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Antigen Processing and MHC Association


Display of foreign peptides complexed with MHC class II versus MHC class I may mean the difference
between life and death for a host cell. Hence it is critical that peptides from exogenous antigens
associate with MHC class II and peptides from endogenous antigens associated with MHC class I.
Therefore, two separate pathways have evolved for the intracellular processing and MHC association
of endogenous versus exogenous antigens. These two separate pathways ensure that endogenous
antigens associate with MHC class I, whereas exogenous antigens associate with MHC class II.

Endogenous Pathway Exogenous Pathway

Endogenous Pathway
Also known as the cytosolic pathway. The processes are as follows:

1. The virus produces viral proteins in the cell.

2. These viral proteins are passed through a multicomponent complex known as the
proteosomes. The viral proteins are degraded into smaller peptide fragments.

Antigen Processing and MHC Association

3. The association between the peptide fragments and MHC class I occurs in the endoplasmic

4. A vesicle then buds off from the endoplasmic reticulum and proceeds to Golgi apparatus for
further conformational change in the MHC I-peptide complex. Then from the Golgi
apparatus, the complex travels to the surface of the cell as secretory vesicle.

5. The peptide-MHC I complex is then displayed at the cell surface.

Action of proteasome

The proteins produced in the cells are broken down into peptides in the cytosol by the proteasome
(multifunctional protease complex) or by other proteases into chains of 8-13 amino acids. The
protease targets these proteins by covalent linkage with a small protein known as ubiquitin. The
ubiquitinating enzymes join with other ubiquitin molecules to a lysine amino group near the amino
terminus of the protein. Subunits of the proteasome, LMP2 and LMP7 that are encoded by the MHC
gene cluster induce the proteolytic complexes to generate peptides that bind well with class I MHC

Transporting the Peptide

The generated peptides travel to the rough endoplasmic reticulum (RER). This enables the peptides
to bond with the class I MHC molecules. TAP (transporters associated with antigen processing) an
important protein of length reaching the membrane of the rough endoplasmic reticulum, helps
transports the peptides into the endoplasmic reticulum.

Binding of the MHC molecule to the Peptide

Once in the ER, Calnexin, a type of chaperone proteins known to aid in the folding of peptides, and
immunoglobulin binding protein (BiP) assist the suitable folding of the class I MHC and associates it
with the β2 micro-globulin. This semi folded class I MHC molecule then interacts with the TAP
initiating the capture of the peptide by the MHC heterodimer, consequently detaching from the
calnexin. The stabilized MHC-antigen complex is ultimately transported to the Golgi complex. Once
at the cell surface, it stimulates the destruction of the cell by attaching to activated CD8+ T C cells.

Exogenous Pathway
Also known as the endocytic pathway. The processes are as follows:

1. An exogenous antigen is engulfed where the plasma membrane invaginates and pinches off
to form a vesicle that contains materials from outside of the cell.

2. These vesicle fuses with the MHC class II molecule that is transported from the endoplasmic
reticulum to Golgi apparatus. The antigen is degraded at this stage and a portion of proteins
of the antigen is attached to the MHC II forming a peptide-MHC II complex.

3. The peptide-MHC II complex is then presented on the cell surface.

Antigen Processing and MHC Association

The Action of the Endosome

For Exogenous antigens (such as bacteria) or foreign particles, are ingested by antigen-presenting
cells (APCs) such as macrophages, dendritic cells and B lymphocytes by endocytosis. Once
internalized, the proteins become acidic by the increasingly acidic endosomal environments: early
endosomes (pH 6.0-6.5), late endosomes (pH 5.0-6.0), and lysosomes (pH4.5-5.0). This allows the
acid-dependant protease to break the proteins into peptides of 13-18 amino acid chains.

MHC Class II Transport

The emerging class II MHC in the endoplasmic reticulum is prevented from binding to the
endogenous antigens by a protein called the invariant (Ii) chain that binds to the peptide-binding
cleft of the class II MHC molecule. The invariant chain also assists the class II MHC with the folding of
the α and β chains and exports it into a vesicle to move to the endocytic compartments.

Binding of the MHC Class II and Peptide

The class II MHC-invariant chain complex moves to an early endosome. Progressive acidification of
the endocytic vesicle leads to the degradation of the invariant chain by proteases leaving behind a
fragment of the invariant chain known as CLIP (class II-associated invariant chain peptide) bound to
the class II MHC. The vesicle of the antigen proteins combines with the vesicle containing the class II
MHC. However, CLIP prevents the antigen proteins from binding with the MHC molecule. This is to
prevent premature interaction with incomplete-processed antigen. The CLIP molecule is removed by
HLA-DM, a class II MHC-like molecule, allowing the MHC to bind with antigens. The MHC-antigen
complex moves to the plasma membrane, a neutral environment that stabilizes the complex. On the
cell surface, it is recognized by CD4+ TH cells.


Antigen processing and presentation is a process that expresses how the antigens are detected by
the immune system. The pathways differ for antigens that are derived from the intracellular
(endogenous) proteins in the cytosol or extracellular (exogenous) proteins. After this process the
antigens are detected by the appropriate T-lymphocyte for the proper removal of the foreign


Basic Immunology. Jacqueline Sharon, PH.D..William & Wilkins. 1998. Michigan

The World Book Encyclopedia (Volume 10). World Book Inc. 2000. Michigan (120908)

http://highered.mcgraw- (300808) (280808)