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

Ludwinski, M.W., Sun, J., Hilliard, B., Gong, S., Xue, F., Carmody, R.J. , DeVirgiliis, J. and Chen, Y.H. (2009) Critical roles of Bim in T cell activation and T cell–mediated autoimmune inflammation in mice. Journal of Clinical Investigation, 119(6), pp. 1706-1713. (doi: 10.1172/JCI37619)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Carmody, Dr Ruaidhri
Authors: Ludwinski, M.W., Sun, J., Hilliard, B., Gong, S., Xue, F., Carmody, R.J., DeVirgiliis, J., and Chen, Y.H.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
Published Online:01 May 2009
Copyright Holders:Copyright © 2009 Americal Society for Clinical Investigation
First Published:First published in Journal of Clinical Investigation 119(6):1706-1713
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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