Critical roles of Bim in T cell activation and T cell–mediated autoimmune inflammation in mice
Maciej W. Ludwinski, Jing Sun, Brendan Hilliard, Shunyou Gong, Fan Xue, Ruaidhri J. Carmody, Jennifer DeVirgiliis, Youhai H. Chen
Maciej W. Ludwinski, Jing Sun, Brendan Hilliard, Shunyou Gong, Fan Xue, Ruaidhri J. Carmody, Jennifer DeVirgiliis, Youhai H. Chen
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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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Figure 1

Effects of Bim deficiency on the development of autoimmune encephalomyelitis.

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Effects of Bim deficiency on the development of autoimmune encephalomyel...
Five -to six-week-old WT and Bim–/– C57BL/6 mice (n = 6) (A), irradiated CD45.1+ WT and CD45.2+Bim–/– C57BL/6 mice (n = 6) that received CD45.1+ WT bone marrow (B), and irradiated CD45.1+ WT C57BL/6 mice (n = 6) that received CD45.1+ WT or CD45.2+Bim–/– bone marrow (C) were immunized with MOG to induce EAE as described in Methods. Data are presented as mean ± SD of EAE scores and are representative of 2–3 independent experiments. The differences between WT and Bim–/– groups are statistically significant (P < 0.001) for panels A and C but not B.