Antigen Processing and Presentation

Formation of peptide-MHC complexes requires degradation of protein antigens into peptides, displayed within the MHC molecule cleft on the cell membrane.
Antigen processing: degradation of protein antigens into peptides.
Antigen presentation: display of transported peptide-MHC molecules on the cell membrane.

Class I MHC:
- Binds peptides from endogenous antigens.
- Processed in the cytoplasm.
- Presented to CD8+ T cells.
Class II MHC:
- Binds peptides from exogenous antigens.
- Internalized by endocytosis.
- Processed within the endocytic pathway.
- Presented to CD4+ T cells.

Calnexin: chaperone, assists in protein folding and promotes assembly with $β2m$ before replacement by calreticulin.
Peptide loading complex: MHC Class I, calreticulin, Erp57, tapasin, and TAP1/2.
- Calreticulin: folding of MHC Class I, required for tapasin binding.
- Erp57: folding of the $a$ chain, in particular $a3$ .
- Tapasin: mediates interaction between newly-assembled MHC class I molecules and TAP1/2.
- TAP1/2: transporter associated with antigen processing, controls cytosolic peptide entry into ER.
Proteosome: ATP-dependent degradation of proteins; 10% of proteins produced are optimal length 8-10 a.a; 7 rings of b subunits (active site), 2 outer rings of a subunits
TAP1/2 entry: proposed to be ATP and ADP dependent; prior to peptide entry the TAP pore is only open on the cytosolic surface.

MHC class II $a$ & $b$ chains assembled in the ER with transmembrane invariant chain.
Invariant chain (li) prevents other proteins or peptides in the ER from binding to MHC class II, chaparone for folding, the MHC $ab$ + li inactivates the ER retention signal and allows transport to the golgi.
li cytopolasmic targeting motifs deliver the class II containing vesicle to the endocytic pathway through the golgi apparatus
Progressive acidification of endocytic vesicle (MHC Class II enriched compartments-MIICs) leads to cathepsin mediated cleavage of li except for a small peptide class II-associated invaraint chain peptide (CLIP).
Exogenous proteins taken up by endocytosis, enter early endosomes with progressive acidification and degradation to peptides by cathepsins
Late endosomes fuse with the MHC Class II enriched compartments- MIICs
A MHC related molecule DM removes CLIP and keeps the peptide cleft open so the peptides generated in the endosome can be inserted
DM may also act as a peptide editor to ensure high affinity peptides bind
In B cells an additional protein DO associates with DM to favour presentation of antigens internalised by the BCR
MHC Class II peptide complexes transported to the surface

Up to 25% of class I molecules present exogenous antigen and 20% of Class II molecules present endogenous antigen
Naive CD8 T cells need DCs to be activated but most viruses don’t infect DCs therefore not present in cytosol
For Class I cross presentation via Sec 61 (ER protein translocator? Also seen in macrophages
For Class II cross presentation- via autophagy “self-eating”; cytosolic antigens engulfed by autophagosome, happens constituatively in APCs and can fuse with the MIICs and follow standard exogenous pathway

Interference with T cell receptor recognition: m04/gp34 (murine cytomegalovirus) binds to MHCI in the ER, steric inhibition of TcR binding
Prevention of peptide transport by TAP: ICP47 (Herpes simplex virus), US6 TAP (human cytomegalovirus), UL49.5 (Varicelloviruses).
Retention of MHC I complexes in the ER: E19 (Adenovirus) interacts with MHC I complex in ER and retains them via a KKXX ER- retention motif, also a tapasin inhibitor
Blocking recognition of MHC class II products: gp42 (Epstein-Barr virus) secretion, binding to HLA-DR (co-receptor for EBV infection), steric hindrance, cant be seen by CD4 TCR.