Critical roles of Bim in T cell activation and T cell–mediated autoimmune inflammation in mice
Maciej W. Ludwinski, … , Jennifer DeVirgiliis, Youhai H. Chen
Maciej W. Ludwinski, … , Jennifer DeVirgiliis, Youhai H. Chen
Published May 1, 2009
Citation Information: J Clin Invest. 2009;119(6):1706-1713. https://doi.org/10.1172/JCI37619.
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Research Article Autoimmunity

Critical roles of Bim in T cell activation and T cell–mediated autoimmune inflammation in mice

Abstract

Bim, the B cell lymphoma 2–interacting (Bcl2-interacting) mediator, maintains immunological tolerance by deleting autoreactive lymphocytes through apoptosis. We report here that Bim is also, paradoxically, required for the activation of autoreactive T cells. Deletion of Bim in hematopoietic cells rendered mice resistant to autoimmune encephalomyelitis and diabetes, and Bim-deficient T cells had diminished cytokine production. Upon T cell receptor activation, Bim-deficient T cells exhibited severe defects in both calcium release and dephosphorylation of nuclear factor of activated T cells (NFAT) but maintained normal levels of activation of NF-κB and MAPKs. The defective calcium signaling in Bim-deficient T cells was associated with a significant increase in the formation of an inhibitory complex containing Bcl2 and the inositol triphosphate receptor (IP3R). Thus, in addition to mediating the death of autoreactive T cells, Bim also controlled T cell activation through the IP3R/calcium/NFAT pathway. These results indicate that a single protein is used to control both the activation and apoptosis of autoreactive T cells and may explain why Bim-deficient mice do not reject their own organs despite lacking thymic negative selection.

Authors

Maciej W. Ludwinski, Jing Sun, Brendan Hilliard, Shunyou Gong, Fan Xue, Ruaidhri J. Carmody, Jennifer DeVirgiliis, Youhai H. Chen

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