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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 (IP^sub 3^R). Thus, in addition to mediating the death of autoreactive T cells, Bim also controlled T cell activation through the IP^sub 3^R/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.
Nonstandard abbreviations used: Bcl2, B cell lymphoma 2; BH, Bcl2 homology; CY, cyclophosphamide; IP^sub 3^R, inositol triphosphate receptor; LDA, limiting dilution analysis; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; NFAT, nuclear factor of activated T cells; PMA, phorbol myristate acetate; STZ, streptozotccin; T1D, type 1 diabetes.
Introduction
Apoptosis, or programmed cell death, is essential for the maintenance of cellular homeostasis in multicellular organisms. It is characterized by a controlled destruction of cellular structures through proteolysis of vital cellular components. Apoptosis can be mediated by at least 2 distinct pathways: the mitochondrial pathway (also called the stress or intrinsic pathway) and the death receptor pathway (also called the extrinsic or mitochondria-independent pathway). Unlike the death receptor pathway, which is activated by death ligands, the mitochondrial pathway is activated by agents that perturb, either directly or indirectly, the integrity of the mitochondrial outer membrane. These include cytotoxic cytokines, antigens, and reactive oxygen species (1-3). The "stressed" mitochondria release cytochrome c to the cytosol, which in turn activates the caspase cascade through Apaf-1 and caspase-9 (4). Unlike the death receptor pathway, the mitochondrial pathway is direcdy controlled by the B cell lymphoma 2 (Bcl2) family of...