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Cathepsin L is essential for onset of autoimmune diabetes in NOD mice
René Maehr, … , Christophe Benoist, Hidde L. Ploegh
René Maehr, … , Christophe Benoist, Hidde L. Ploegh
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2934-2943. https://doi.org/10.1172/JCI25485.
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Research Article Immunology Article has an altmetric score of 2

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

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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-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.

Authors

René Maehr, Justine D. Mintern, Ann E. Herman, Ana-Maria Lennon-Duménil, Diane Mathis, Christophe Benoist, Hidde L. Ploegh

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Figure 1

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Cat L–deficient mice are protected from pancreatic insulitis. (A) Diabet...
Cat L–deficient mice are protected from pancreatic insulitis. (A) Diabetes frequency was determined by measurement of urine glucose levels in Cat L–deficient (Cat L–/–, open squares, n = 13), Cat L–heterozygous (Cat L+/–, open circles, n = 23), and Cat L–wild-type (Cat L+/+, filled squares, n = 9) female NOD mice. *Statistical analysis by the χ2 test yielded a value of P < 0.001 for diabetes incidence in 29-week-old Cat L–deficient compared with wild-type NOD mice. (B) At 10–11 weeks of age, Cat L–deficient mice (–/–) together with control wild-type (+/+) and heterozygous (+/–) littermates were analyzed for insulitis by scoring histological analysis. Insulitis was characterized as peri-, nonextensive, or extensive depending on the level of infiltration. Peri-insulitis is reflected as a noninvasive leukocyte accumulation outside the pancreatic islet whereas nonextensive insulitis describes an invasive infiltrate in the pancreatic islet. In extensive insulitis, more than 50% of the individual pancreatic islet is infiltrated or destroyed. Each bar represents an individual mouse. (C and D) At 14–19 weeks of age, male and female Cat L–deficient animals and control littermates were analyzed for infiltration of the pancreas. (E) Levels of insulitis present in 23- to 38-week-old Cat L–deficient NOD mice and control littermates were determined. Mice examined in the 23- to 38-week age groups were female except for 2 Cat L–deficient male NOD mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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