Proteases involved in MHC class II antigen presentation

Major histocompatibility complex class Ii antigen presentation requires the participation of lysosomal proteases in two convergent processes. First, t he antigens endocytosed by the antigen-presenting cells must be broken down into antigenic peptides. Second, class II molecules are synthesized with t heir peptide-binding site blocked by invariant chain (Ii), and they acquire the capacity to bind antigens only after Ii has been degraded in the compa rtments where peptides reside. The study of genetically modified mice defic ient in single lysosomal proteases has allowed us to determine their role i n these processes. Cathepsins (Cat) B and D, previously considered major pl ayers in MHC class II antigen presentation, are dispensable for degradation of Ii and for generation of several antigenic determinants. By contrast, C ar S plays an essential role in removal of Ii in B cells and dendritic cell s, whereas Cat L apparently does so in thymic epithelial cells. Accordingly , the absence of Cat S and L have major consequences for the onset of humor al immune responses and for T-cell selection, respectively. It is likely th at other as yet uncharacterized lysosomal enzymes also play a role in Ii de gradation and in generation of antigenic determinants. Experiments involvin g drugs that interfere with protein traffic suggest that more than one mech anism for Ii removal, probably involving different proteases, can co-exist in the same antigen-presenting cell. These findings may allow the developme nt of protease inhibitors with possible therapeutic applications.