Pathways of antigen processing

Pathways of antigen processing: To initiate an immune response, antigenic peptides are presented by MHC I and MHC II to CD8 and CD4 T cells respectively. The endogenous or intracellular pathway processes peptides and prepares them for MHC I, while the exogenous or extracellular pathway processes peptides for MHC II.

i) Endogenous pathway: Viral or self-derived proteins are degraded by cytosolic or nuclear proteasomes. The peptides are then translocated into the endoplasmic reticulum (ER) by TAP. Tapasin, which is a component of the peptide-loading complex, interacts with TAP. Erp57 and calreticulin are other components of the peptide loading complex. This complex facilitates the proper folding of MHC I and its association with beta 2 microglobulin. Once the peptide is in the ER, it is loaded to MHC I and the MHC-peptide complex is transported by the golgi apparatus to the cell surface. Peptides that fail to associate with MHC I are degraded in the cytosol.

ii) Exogenous pathway: It is employed by antigen presenting cells and presents peptides derived from degradation of endocytosed particles. These particles undergo lysis in the endosomes by acid-dependent proteases. The peptides are loaded on MHC II and presented to T cells. MHC II is composed of alpha and beta chains and an invariant chain. They are synthesized in the ER and are transported through the Golgi into a compartment called MIIC or MHC class II compartment. The acidic pH in MIIC activates proteases like cathepsins which digest the invariant chain, leaving remnant called CLIP. The peptide binding groove is filled with CLIP, which is later on exchanged and the peptide processed by the exogenous pathway is loaded on MHC II. HLA DM and HLA DO molecules assist in loading.