Critical roles of Bim in T cell activation  and T cell-mediated autoimmune  inflammation in mice.
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-kappaB 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.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Maciej W
MW
Ludwinski
Jing
J
Sun
Brendan
B
Hilliard
Shunyou
S
Gong
Fan
F
Xue
Ruaidhri J
RJ
Carmody
Jennifer
J
DeVirgiliis
Youhai H
YH
Chen
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D020278:Demyelinating Autoimmune Diseases, CNS / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000276:immunology; D010179:Pancreas / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D008565:Membrane Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D002118:Calcium