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 (intracellular) pathway processes peptides for MHC I, while the exogenous (extracellular) pathway processes peptides for MHC II.
i) Endogenous pathway: Viral or self-derived proteins are degraded by proteasomes in the cytosol or nucleus. The resulting peptides are translocated into the endoplasmic reticulum (ER) by TAP. Tapasin, a component of the peptide-loading complex, interacts with TAP. Erp57 and calreticulin are other components of this peptide-loading complex.
This complex helps MHC I fold correctly and associate with beta 2 microglobulin. Once the peptide is in the ER, it’s loaded onto MHC I. The MHC-peptide complex is then transported through the Golgi apparatus to the cell surface. Peptides that fail to associate with MHC I are degraded in the cytosol.
ii) Exogenous pathway: This pathway is used by antigen-presenting cells and presents peptides derived from the degradation of endocytosed particles. These particles undergo lysis in endosomes by acid-dependent proteases. The resulting peptides are loaded onto MHC II and presented to T cells.
MHC II is composed of alpha and beta chains and an invariant chain. These are synthesized in the ER and transported through the Golgi into a compartment called MIIC (MHC class II compartment). The acidic pH in MIIC activates proteases such as cathepsins, which digest the invariant chain and leave a remnant called CLIP. CLIP occupies the peptide-binding groove and is later exchanged so that the peptide processed by the exogenous pathway can be loaded onto MHC II. HLA DM and HLA DO molecules assist in loading.
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