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

Balasubramanian Krishnamurthy, Jonathan Chee, Gaurang Jhala, Prerak Trivedi, Tara Catterall, Claudia Selck, Esteban N. Gurzov, Thomas C. Brodnicki, Kate L. Graham, Jibran A. Wali, Yifan Zhan, Daniel Gray, Andreas Strasser, Janette Allison, Helen E. Thomas, Thomas W.H. Kay

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Because regulatory T-cell (Treg) development can be induced by the same agonist self-antigens that induce negative selection, perturbation of apoptosis will affect both negative selection and Treg development. But how the processes of thymocyte deletion versus Treg differentiation bifurcate and their relative importance for tolerance have not been studied in spontaneous organspecific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, BIM, in the 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 IkB-a in thymocytes from NODBim-/- mice suggest that autoreactive cells receiving strong T-cell receptor 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 antigenspecific Tregs and prevent autoimmune disease.

Original languageEnglish
Pages (from-to)3229-3238
Number of pages10
JournalDiabetes
Volume64
Issue number9
DOIs
Publication statusPublished - 1 Sep 2015
Externally publishedYes

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    Krishnamurthy, B., Chee, J., Jhala, G., Trivedi, P., Catterall, T., Selck, C., Gurzov, E. N., Brodnicki, T. C., Graham, K. L., Wali, J. A., Zhan, Y., Gray, D., Strasser, A., Allison, J., Thomas, H. E., & Kay, T. W. H. (2015). BIM deficiency protects NOD mice from diabetes by diverting thymocytes to regulatory T cells. Diabetes, 64(9), 3229-3238. https://doi.org/10.2337/db14-1851