The role of cysteine proteases in MHC class II antigen processing and presentation

MHC class II molecules present self and foreign antigenic peptides to CD4+ T cells. Specific lysosomal cysteine proteases cathepsin S and cathepsin L are critical for the processing of antigens and are required for the maturation of the MHC class II by degrading the chaperone molecule invariant chain. There is a distinct distribution of these cysteine proteases with cathepsin S expressed in bone marrow derived antigen presenting cells and cathepsin L in thymic epithelium. Macrophages are unique because they contain both active cathepsin S and cathepsin L. Interestingly, macrophages activated to upregulate MHC class II levels on the cell surface with the type-I immune cytokine IFN-gamma, markedly decreases cathepsin L activity to below levels of detection whereas, mature cathepsin L protein levels remain unchanged. Furthermore, our results suggest that there is a potential specific inhibitor of cathepsin L activity. Cathepsin S activity, however, increases in response to treatment with IFN-gamma and in its absence we find an accumulation of invariant chain fragments. Therefore, cathepsin S is responsible for antigen processing and presentation in macrophages. This demonstrates cysteine protease activity is non-redundant and tightly controlled not only by expression but by strategically expressed inhibitors in professional antigen presenting cells.; Non-professional antigen presenting cells have been shown to express low levels of MHC class II or can be induced to transiently express MHC class II on the cell surface. We examined MHC class II levels and invariant chain degradation in mice deficient in either cathepsin S or cathepsin L. Surprisingly, increased MHC class II and accumulated invariant chain fragments were detected in the epithelium of the small and large intestine mice devoid of cathepsin S. We were able to demonstrate for the first time that freshly isolated epithelial cells are capable of internalizing and presenting endogenous antigens and more importantly, that cathepsin S is prominent in this process. Moreover, deficiency in cathepsin L does not affect invariant chain processing or MHC class II levels in epithelial cells lining the intestine. Thus, we have described that all MHC class II antigen presenting cells utilize cathepsin S for invariant chain processing and antigen presentation.