René Maehr, Justine D. Mintern, Ann E. Herman, Ana-Maria Lennon-Duménil, Diane Mathis, Christophe Benoist, Hidde L. Ploegh
J Clin Invest.
2005;
115(10):2934–2943
doi:10.1172/JCI25485
This article Copyright © 2005, The American Society for Clinical Investigation
Abstract
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L
ysosomal 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-Ag7–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.
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