Fundamentals of Microbiology & Immunology (MIM 425)
Lecture # 11, March 22, 2007 by Zheng W. Chen, M.D.,Ph.D
Antigen presentation to T cells:
Intracellular compartments in APC for generation of TCR ligands (MHC-peptide
complexes)
Cytosol; the compartment for MHC class I antigen presentation pathway; viruses and some
intracellular bacteria can replicate in cytosol, and peptides from these pathogens are
processed here, bound to MHC class I and presented to cell-surface as ligands recognized by
TCR on CD8 T cells. The ligand-specific MHC class I-restricted CD8 T cells are cytotoxic killer
cells, recognizing and destroying the virus-infected target cells (macrophages/monocytes,
dendritic cells,B cells).
Vesicular system—MHC class II Ag presentation pathway; considered as continuous with the
extracellular fluid, extracellular material is taken out by endocytosis into endosomes, which
then move to lysosome for degradation. Extracellular bacteria or viruses as well as their
proteins in the circulation (bacteremia and viremia) can be uptaken by APC through
phagocytosis, endocytosis or macropinocytosis into the intracellular vesicles, bound to MHC
class II and then presented to CD4 T cells
Typical MHC class I pathway for antigen peptide processing and presentation
An antigen peptide binding to the MHC class I molecule takes place in endoplasmic reticulum
(ER).
MHC class I molecules do not leave the ER unless they bind peptides.
Newly-synthesized MHC class I chains bind to a chaperone protein, calnexin, before 2-
microglobulin (2 m) binds.
Then MHC class I : 2 m complex is released from calnexin, bind a complex of chaperone
proteins (calreticulin, Erp57), and binds to peptide transporter TAP (transporters associated
with antigen processing) by interacting with tapasin (TAP-associated protein). This complex
now makes it possible for TAP to deliver antigen peptides from the cytosol and then for the
peptide to bind to MHC class I.
Viral proteins in the cytosol are degraded or trimmed into small peptide fragments. This
cytosolic protein degradation is carried out by a large, multicatalyic protease complex called
proteasome.
The peptide fragments are transported to the ER by TAP-1 and -2.
Once MHC class I : 2 m complex is loaded with a specific peptide, this complex becomes
fully folded, released from the TAP complex, exported from the ER and stably expressed on
the cell surface.
MHC class II pathway for antigen peptide processing and presentation
Processing takes place in the vesicular system.
MHC class II molecules in the ER cannot bind to peptides in the ER because newly-
synthesized MHC class II molecules are associated with the invariant chain (Ii) that fills and
blocks their peptide-binding groove.
The MHC class II : Ii complexes are driven by Ii to acidified intracellular vesicles, in which a
short peptide fragment (CLIP) from Ii still occupy the class II peptide-binding groove.
1
Endocytosed proteins or pathogens are degraded to peptides in endosomes, and the
endosomes are fused with the vesicles containing CLIP-loaded MHC class II molecules. CLIP
blocks the binding of peptides to MHC class II molecules.
In the acidic endosomes, a specialized MHC class II-like molecule, HLA-DM, catalyzes both
the release of the CLIP from MHC class II peptide-binding groove and the binding of degraded
peptides in endosomes to the MHC class II peptide-binding groove.
MHC class II: peptide complex thus travels to the cell surface.
Both MHC class I and II must bind to peptides in order to stably express on the cell-surface.
2