The role of lysosomal proteinases in MHC class II-mediated antigen processing and presentation

Abstract

The recent analysis of cathepsin-deficient mice has shed light upon the role of lysosomal proteinases in the MHC class II processing and presentation pathway. Ubiquitous expression and involvement in the terminal degradation of proteins that intersect the endocytic pathway were previously perceived to be the hallmarks of these proteinases. However, recent evidence has demonstrated that several cathepsins are expressed in a tissue-specific fashion and that partial proteolysis of specific biological targets is a key function of cathepsins in antigen processing. Our work has focused on the differential expression of the cysteine proteinases cathepsins L (CL) and S (CS) and its pertinence to the generation of MHC class II: peptide complexes. Analysis of CL-deficient mice revealed a profound defect in invariant chain degradation in thymic cortical epithelial cells but not in bone marrow-derived antigen-presenting cells (APCs) (B cells, dendritic cells, and macrophages). The tissue-specific deficiency reflected the restricted pattern of expression of CL and CS in these cell types--CL is expressed in thymic cortical epithelial cells but not in DC or B cells, while CS exhibits the opposite expression pattern. The differential expression of proteinases by distinct APCs may affect the types of peptides that are presented to T cells and thereby the immune responses that are ultimately generated.