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Lysosomal proteases generate peptides presented by class II MHC molecules to CD4^sup +^ T cells. To determine whether specific lysosomal proteases might influence the outcome of a CD4^sup +^ 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^sup g7^-restricted CD4^sup +^ T cells are diminished in Cat L-deficient mice, although a potentially diabetogenic T cell repertoire persists. Within the CD4^sup +^ 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^sup +^ 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.
Nonstandard abbreviations used: Cat, cathepsin; CIITA, class II transactivator; CLIP, class II-associated invariant chain peptide; cTEC, cortical thymic epithelial cell; Ii, invariant chain; LHVS, N-morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl; SLIP, small leupeptin-induced peptide.
Introduction
IDDM, or type 1 diabetes, is an autoimmune disease characterized by destruction of insulin-producing β cells in the islets of Langerhans (1). in humans and mice, the MHC region, in particular the class II MHC region, is a key susceptibility locus strongly associated with the disease (reviewed in refs. 2,3). In humans, both HLA-DR and -DQ are associated with susceptibility to type 1 diabetes. In NOD mice, a structurally similar class II MHC molecule, I-A^sup g7^, contributes to disease susceptibility (reviewed in refs. 3, 4).
The class II MHC locus encodes molecules that bind antigenic peptides for presentation to CD4^sup +^ T cells. Class II MHC molecules are coassembled in the endoplasmic reticulum with a chaperone, the invariant chain (Ii). In endocytic compartments, Ii is progressively proteolyzed to yield a class II MHC-bound Ii remnant referred to as class II-associated invariant chain peptide (CLIP). Removal of CLIP by an accessory molecule, the nonclassical class II-dimer, H-2M, is required to allow peptide loading (reviewed in ref. 5). Interference with the proteolysis of Ii inhibits the formation of peptide-loaded class II MHC molecules (6-8)...