Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules 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 of secretory granule proteins 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 (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.

Automated summary

The identification of peptide epitopes presented by MHCII molecules that drive CD4 T cell autoimmunity, particularly in type 1 diabetes, has been a challenge. Recent insights suggest that important epitopes are actually chimeric epitopes pieced together from different peptide fragments, rather than directly processed from a protein source. This fusion process, known as transpeptidation, may occur during the catabolic turnover of pancreatic proteins, shedding light on how self-tolerance can be broken peripherally in autoimmune diseases like T1D.