Cathepsin L is essential for onset of autoimmune diabetes in NOD mice

Abstract

Lysosomal proteases generate peptides presented by class II MHC molecules to CD4⁺ T cells. To determine whether specific lysosomal proteases might influence the outcome of a CD4⁺ T cell–dependent autoimmune response, we generated mice that lack cathepsin L (Cat L) on the autoimmune diabetes-prone NOD inbred background. The absence of Cat L affords strong protection from disease at the stage of pancreatic infiltration. The numbers of I-A^g7–restricted CD4⁺ T cells are diminished in Cat L–deficient mice, although a potentially diabetogenic T cell repertoire persists. Within the CD4⁺ T cell compartments of Cat L–deficient mice, there is an increased proportion of regulatory T cells compared with that in Cat L–sufficient littermates. We suggest that it is this displaced balance of regulatory versus aggressive CD4⁺ T cells that protects Cat L–deficient mice from autoimmune disease. Our results identify Cat L as an enzyme whose activity is essential for the development of type I diabetes in the NOD mouse.