Antigen processing

Antigen processing is a biological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens (e.g. viruses), or from phagocytosed pathogens (e.g. bacteria); subsequent presentation of these antigens on class I or class II MHC molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigen before they are stably expressed on a cell surface.

While the conventional distinction between the two pathways is useful, there are instances where extracellular-derived peptides are presented in the context of MHC class I and cytosolic peptides are presented in the context of MHC class II (this often happens in dendritic cells).

The Endogenous Pathway
The endogenous pathway is used to present cellular peptide fragments on the cell surface on MHC class I molecules. If a virus had infected the cell, viral peptides would also be presented, allowing the immune system to recognize and kill the infected cell. Worn out proteins within the cell become ubiquitinated, marking them for proteasome degradation. Proteasomes break the protein up into peptides that include some around nine amino acids long (suitable for fitting within the peptide binding cleft of MHC class I molecules). Transporter associated with antigen presenting (TAP), a protein that spans the membrane of the rough endoplasmic reticulum, transports the peptides into the lumen of the rough endoplasmic reticulum (ER). Also within the rough ER, a series of chaperone proteins, including calnexin, calreticulin, ERp57, and Binding immunoglobulin protein (BiP) facilitates the proper folding of class I MHC and its association with β2 microglobulin. The partially folded MHC class I molecule then interacts with TAP via tapasin (the complete complex also contains calreticulin and Erp57 and, in mice, calnexin). Once the peptide is transported into the ER lumen it binds to the cleft of the awaiting MHC class I molecule, stabilizing the MHC and allowing it to be transported to the cell surface by the golgi apparatus.

The Exogenous Pathway
The exogenous pathway is utilized by specialized antigen presenting cells to present peptides derived from proteins that the cell has endocytosed. The peptides are presented on MHC class II molecules. Proteins are endocytosed and degraded by acid-dependent proteases in endosomes; this process takes about an hour.

The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by Ii (the invariant chain; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway. The invariant chain also facilitates MHC class II's export from the ER in a vesicle. This fuses with a late endosome containing the endocytosed, degraded proteins. It is then broken down in stages, leaving only a small fragment called CLIP which still blocks the peptide binding cleft. An MHC class II-like structure, HLA-DM, removes CLIP and replaces it with a peptide from the endosome. The stable MHC class-II is then presented on the cell surface.

In Cross-presentation, peptides derived from extracellular proteins are presented in the context of MHC class I.