Lysosomal Protease Creation of Chimeric Epitopes for Diabetogenic CD4 T cells via Transpeptidation

Abstract

The identification of the peptide epitopes presented by major histocompatibility complex class II molecules (MHCII) that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type-1 diabetes (T1D) recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes. Here we demonstrate that highly antigenic chimeric epitopes for diabetogenic CD4 T cells are produced by digestion of the appropriate fragments of the diabetogenic granule proteins with the lysosomal protease, cathepsin L (CatL). This pathway has implications for how self-tolerance can be broken in T1D and other autoimmune diseases.