Antigen Processing and Presentation

Study Notes

Antigen processing involves two main pathways: MHC class I and MHC class II
The endogenous pathway (MHC class I): processes intracellular antigens
- Intracellular proteins are degraded into peptides by the proteasome.
- Peptides are transported into the endoplasmic reticulum via TAP.
- Peptides bind to MHC class I molecules.
- MHC class I-peptide complexes are presented on the cell surface to CD8+ T cells.
The exogenous pathway (MHC class II): processes extracellular antigens
- Extracellular antigens are taken up by endocytosis, forming endosomes or lysosomes.
- Antigens are degraded to peptides.
- Peptides bind to MHC class II molecules.
- MHC class II-peptide complexes are presented on the cell surface to CD4+ T cells.

Proteasome: A large, multicatalytic protease complex (~28 subunits) that degrades cytosolic proteins.
TAP Transporter (transporter associated with antigen processing): A heterodimer of TAP-1 and TAP-2 proteins.
- Transports peptides across the endoplasmic reticulum (ER).
Calnexin: An ER membrane-bound protein (88 kDa) that retains MHC class I molecules in the ER until the peptide is bound. It acts as a chaperone protein.
Peptide Loading Complex (PLC): A complex of chaperone proteins
- Calreticulin: Similar function to calnexin
- Tapasin: Links MHC Class I to TAP.
- ERp57: Mediates peptide binding to Class I.
Endoplasmic Reticulum Aminopeptidase associated with Antigen Processing (ERAAP): Trims peptides to the correct length.

Associates with newly formed MHC class II molecules to prevent peptide binding in the ER.
Targets delivery of new Class II molecules to low pH endosomes.

Partly folded MHC class I α chains bind to calnexin until β2-microglobulin binds.
MHC class I α:β2m complex is released from calnexin.
Binds a complex of chaperone proteins (calreticulin, ERp57) and TAP via tapasin.
Cytosolic proteins (and defective ribosomal products) are degraded to peptide fragments by the proteasome.
TAP delivers peptides to the ER.
A peptide binds MHC class I molecule and completes its folding.
The MHC class I molecule is released from the TAP complex and exported to the cell membrane.
Normal proteins (>70%) vs. DRIPs (<30%).

Invariant chain (li, CD74) forms a complex with MHC class II molecules blocking peptide binding and misfolded protein binding.
li is cleaved in an acidified endosome; leaving a short peptide fragment (CLIP) still bound to MHC class II.
Endocytosed antigens are degraded to peptides in endosomes; CLIP blocks antigen binding to MHC II.
HLA-DM binds to MHC II molecule, releasing CLIP, allowing other peptides to bind.
MHC II molecule travels to the cell surface.