Bim deficiency protects NOD mice from diabetes by diverting thymocytes to regulatory T cells

Krishnamurthy, B; Chee, J; Jhala, G; Trivedi, P; Catterall, T; Selck, C; Gurzov, EN; Brodnicki, TC; Graham, KL; Wali, JA; Zhan, Y; Gray, D; Strasser, A; Allison, J; Thomas, HE; Kay, TW

Author(s): Krishnamurthy, B; Chee, J; Jhala, G; Trivedi, P; Catterall, T; Selck, C; Gurzov, EN; Brodnicki, TC; Graham, KL; Wali, JA; Zhan, Y; Gray, D; Strasser, A; Allison, J; Thomas, HE; Kay, TW;
Details: Publication Year 2015-05-06,Volume 64,Issue #9,Page 3229-3238
Journal Title: Diabetes
Publication Type: Journal Article
Abstract: Because regulatory T (Treg) cell development can be induced by the same agonist self antigens that induce negative selection, perturbation of apoptosis will impact both negative selection and Treg cell development. But how the processes of thymocyte deletion versus Treg cell differentiation bifurcate and their relative importance for tolerance has not been studied in spontaneous organ-specific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, Bim, in the non-obese diabetic (NOD) mouse model of autoimmune diabetes. Despite substantial defects in the deletion of autoreactive thymocytes, Bim deficient NOD (NODBim-/-) mice developed less insulitis and were protected from diabetes. Bim deficiency did not impair effector T cell function, however, NODBim-/- mice had increased numbers of Tregs, including those specific for proinsulin, in the thymus and peripheral lymphoid tissues. Increased levels of Nur77, CD5, GITR and phosphorylated I-kappaB in thymocytes from NODBim-/- mice suggest that autoreactive cells receiving strong TCR signals that would normally delete them 'escape' apoptosis and are diverted into the Treg pathway. Paradoxically, in the NOD model, reduced thymic deletion ameliorates autoimmune diabetes by increasing Tregs. Thus modulating apoptosis may be one of the ways to increase antigen specific Tregs and prevent autoimmune disease.
Publisher: American Diabetes Association
Research Division(s): Immunology; Molecular Genetics Of Cancer
PubMed ID: 25948683
Publisher's Version: https://doi.org/10.2337/db14-1851
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-05-22 11:19:37

Last Modified: 2015-09-11 09:52:26