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

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-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 3

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Antigen presentation proceeds normally in Cat L–deficient mice. (A) CFSE...
Antigen presentation proceeds normally in Cat L–deficient mice. (A) CFSE-labeled BDC2.5 splenocytes were transferred into wild-type, Cat L–heterozygous, or Cat L–deficient mice. T cell proliferation was assessed 65 hours later by CFSE dilution in the CD4+ T cell population. The percentage of CD4+ T cells that exhibited dilution of CFSE as a result of cell division was determined for cells falling into the region of CFSE-positive cells that underwent at least 1 cell division (indicated by the bar). IngLN, inguinal lymph node; PanLN, pancreatic lymph node. (B) Results of 3 or more independent CFSE transfer experiments are summarized for wild-type (n = 5), Cat L–heterozygous (n = 4), and Cat L–deficient (n = 8) recipients; each point represents an individual mouse. (C) A total of 5 × 105 BDC2.5/NOD donor splenocytes were injected i.p. into Cat L–deficient NOD/Scid mice (n = 4) or wild-type controls (n = 5). Diabetes incidence was determined by urine glucose levels. (D) Splenocytes from recently diabetic mice were injected into sublethally irradiated Cat L–deficient NOD mice or wild-type and heterozygous controls. Insulitis was determined on histological nonconsecutive sections. The number of mice used in the experiments is indicated.