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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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 5

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Cat L–deficient mice exhibit a relative increase of CD4+CD25+ to CD4+CD2...
Cat L–deficient mice exhibit a relative increase of CD4+CD25+ to CD4+CD25– cells. (A) Cytofluorometry analysis of splenic lymphocytes (left 4 panels) for CD4, CD8α, and CD25 surface expression. CD4+ lymphocytes (right 4 panels) are resolved for surface expression of CD25 together with their CD45RB and CD69 expression profiles. (B) Relative Foxp3 expression in CD4+ and CD8α+ lymphocytes was assessed by real-time quantitative PCR. Foxp3 expression was normalized against hypoxanthine-guanine phosphoribosyl transferase expression levels. The data are displayed relative to normalized Foxp3 expression in wild-type CD4+ T cells. The data summarize 3 independent experiments, and the SEM is indicated. The experimental error within an individual experiment was less than 4% for triplicates. (C) Transfer of CD4+CD25+-depleted or -nondepleted splenocytes derived from Cat L–deficient or CD4+CD25+-depleted Cat L–sufficient mice into NOD/Scid hosts. The numbers of NOD/Scid recipients of individual cell suspensions are indicated. Diabetes was determined by urine glucose measurements. The data summarize the results of 3 independent experiments. The χ2 test was used to assess statistical significance, and P values are indicated.