Role of BIM in Type I diabetes

The BCL-2 family of proteins consists of approximately twenty members that function in the stress pathway of apoptosis. Interactions between anti-apoptotic and pro-apoptotic member proteins determine cell fate. Over the years, it has become evident that the interplay between BCL-2 family members affects more than just apoptosis, but also other processes such as proliferation and intracellular calcium signaling. BIM is a pro-apoptotic BCL-2 family member protein that functions in the process of negative selection to delete self-reactive lymphocytes and in clonal contraction following clearance of pathogens. Its role in the apoptosis of self-reactive lymphocytes is believed to be important for the prevention of autoimmunity. Studies with non-obese diabetic mice (NOD) indicate that a defect in BIM expression contributes to Type I diabetes (TID) development in NOD mice. Through studies into TID, we have discovered that BIM deficiency actually prevents TID development. Although BIM knockout mice have more self-reactive T cells than control mice, using limiting dilution analysis we show that the actual “effective frequency” of (β-cell-specific T cells able to respond to antigen is significantly lower. Through analysis of BIM-deficient T cells, we show that BIM plays a role in T cell proliferation and activation. BIM-deficient T cells are defective in TCR-induced intracellular calcium efflux, which results in decreased IL-2 production due to improper NFAT activation. Although BIM knockout mice may have more self-reactive T cells, they are not as “effectively” activated as T cells in wildtype mice when exposed to antigen

Role of BIM in Type I diabetes

The BCL-2 family of proteins consists of approximately twenty members that function in the stress pathway of apoptosis. Interactions between anti-apoptotic and pro-apoptotic member proteins determine cell fate. Over the years, it has become evident that the interplay between BCL-2 family members affects more than just apoptosis, but also other processes such as proliferation and intracellular calcium signaling. BIM is a pro-apoptotic BCL-2 family member protein that functions in the process of negative selection to delete self-reactive lymphocytes and in clonal contraction following clearance of pathogens. Its role in the apoptosis of self-reactive lymphocytes is believed to be important for the prevention of autoimmunity. Studies with non-obese diabetic mice (NOD) indicate that a defect in BIM expression contributes to Type I diabetes (TID) development in NOD mice. Through studies into TID, we have discovered that BIM deficiency actually prevents TID development. Although BIM knockout mice have more self-reactive T cells than control mice, using limiting dilution analysis we show that the actual “effective frequency” of (β-cell-specific T cells able to respond to antigen is significantly lower. Through analysis of BIM-deficient T cells, we show that BIM plays a role in T cell proliferation and activation. BIM-deficient T cells are defective in TCR-induced intracellular calcium efflux, which results in decreased IL-2 production due to improper NFAT activation. Although BIM knockout mice may have more self-reactive T cells, they are not as “effectively” activated as T cells in wildtype mice when exposed to antigen

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-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