Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

J Clin Invest. 2011 May;121(5):1810-21. doi: 10.1172/JCI43314. Epub 2011 Apr 18.


Type 1 diabetes is a chronic autoimmune disease in which genetic predispositions affect the immune system, leading to a loss of T cell tolerance to β cells and consequent T cell-mediated destruction of insulin-producing islet cells. Genetic studies have suggested that PRSS16 is linked to a diabetes susceptibility locus of the extended HLA class I region in humans. PRSS16 encodes what we believe to be a novel protease, thymus-specific serine protease (TSSP), which shows predominant expression in thymic epithelial cells and is suspected to have a restricted role in the class II presentation pathway. Consistently, Tssp is necessary for the intrathymic selection of few class II-restricted T cell receptor specificities in B6 mice. To directly assess the role of Tssp in autoimmune diabetes, we generated Tssp-deficient (Tssp°) NOD mice. While remaining immunocompetent, Tssp° NOD mice were protected from diabetes and severe insulitis. Diabetes resistance of Tssp° NOD mice was a property of the CD4 T cell compartment that is acquired during thymic selection and correlated with an impaired selection of CD4 T cells specific for islet antigens. Hence, in the NOD mouse, Tssp is a critical regulator of diabetes development through the selection of the autoreactive CD4 T cell repertoire.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Genetic Predisposition to Disease
  • Histocompatibility Antigens Class I / chemistry
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Models, Biological
  • Serine Endopeptidases / metabolism*
  • T-Lymphocytes / metabolism
  • Thymus Gland / metabolism


  • Histocompatibility Antigens Class I
  • Prss16 protein, mouse
  • Serine Endopeptidases