title: Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice.
abstract: 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.
authors.affiliation: INSERM, U1043, Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Viret
authors.forename: Stéphane
authors.initials: S
authors.lastname: Leung-Theung-Long
authors.forename: Laurent
authors.initials: L
authors.lastname: Serre
authors.forename: Camille
authors.initials: C
authors.lastname: Lamare
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Alice
authors.initials: A
authors.lastname: Carrier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guerder
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D012697:Serine Endopeptidases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; C472501:Prss16 protein, mouse; D012697:Serine Endopeptidases