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

J Clin Invest. 2005 Oct;115(10):2934-43. doi: 10.1172/JCI25485. Epub 2005 Sep 22.


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-A(g7)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Cathepsin L
  • Cathepsins / genetics
  • Cathepsins / immunology*
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / immunology*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Histocompatibility Antigens Class II / immunology*
  • Lysosomes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Knockout
  • Pancreas / immunology
  • Pancreas / pathology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology


  • Histocompatibility Antigens Class II
  • Cathepsins
  • Cysteine Endopeptidases
  • Cathepsin L
  • Ctsl protein, mouse