How peptides are generated for MHC class i antigen presentation

MHC class I molecules in all cells bind and display to the immune system peptides derived from cellular and viral proteins. This allows the immune system to screen the expressed genes in tissues and destroy cells that are synthesizing foreign proteins. The majority of presented peptides are generated by degradation of proteins in the cytoplasm. The mechanisms responsible for generating these peptides in the cytosol will be discussed. Available evidence indicates that the proteasome, a multicatalytic proteolytic particle, plays a major role in generating these sequences. It has been unknown whether in vivo proteasomes directly produce the final 8 to 9 residue peptides that fit in the antigen binding groove of class I molecules. We now demonstrate in intact cells that cleavage by the proteasome defines the proper C-terminus of SIINFEKL from the antigen ovalbumin. However, a distinct peptidase(s) in the cytosol or endoplasmic reticulum generates the appropriate N-terminus of this epitope. Therefore, there are two distinct proteolytic steps in the generation of an ovalbumin-presented peptide.