Protein degradation in MHC class II antigen presentation: opportunities for immunomodulation

Proteolysis is required for two steps of the MHC class II antigen-processing pathway, degradation of invariant chain and cleavage of protein antigens. Invariant chain dissociation from MHC is limited by a final proteolytic event which is tightly regulated in both temporal and tissue-specific ways. In contrast, enzymes involved in antigen proteolysis remain ill-defined. Gene 'knockout' experiments of housekeeping proteolytic enzymes suggest either that these enzymes do not play a major role, or that antigen proteolysis is too degenerate for this type of analysis. The possible role of two other proteinases, cathepsin E and aspariginyl endopeptidase is discussed. Finally, the data implicating antigen processing in repertoire generation is briefly considered. We conclude that selective regulation of endosomal proteolysis could have profound implications for control of immunity against infection, as well as in autoimmunity.