Regulation of expression of Bcl-2 protein family member Bim by T cell receptor triggering

Abstract

Bim, a proapoptotic BH3-only member of the Bcl-2 protein family, is required for central and peripheral deletion of T lymphocytes. Mechanisms regulating Bim activity in T cells remain poorly understood. We show that expression of Bim is up-regulated in human T cells after polyclonal or specific T cell receptor triggering. Induction of Bim was affected by the agonistic potency of MH-C:peptide ligands. Peptides that failed to induce Bim expression, failed to induce apoptosis in specific T cells, whereas partially agonistic ligands, which trigger death receptor-independent activation-induced cell death (AICD), induced Bim, but were inefficient in up-regulating Bcl-XL. Activation of protein kinase C and calcineurin appeared to be necessary and sufficient for Bim upregulation after T cell receptor ligation. Immunosuppressive drugs known to prevent T cell deletion in vivo, such as cyclosporin A or FK506, blocked Bim up-regulation and rescued T cells from death receptor-independent AICD, whereas rapamycin, which allows the development of stable immunological tolerance, did not exhibit these activities. These results define a new mode of Bim regulation, strongly implicate Bim as a mediator of AICD, and suggest that Bim up-regulation can be targeted to influence the outcome of specific immune responses.apoptosis ͉ epitope

The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling

“…10 Our own studies using human CD8 ϩ T-cell blasts have shown that apoptosis by cytokine deprivation predominates over death receptor ligation and that high levels of Bim expression are necessary for this process to occur. 13 The expression of Bim and Bcl-x S clearly increases during the process of T-cell blast generation, 13,18,52 arriving at maximum levels around day 5 or 6 of stimulation, just at the point where human T-cell blasts begin to be sensitive to apoptosis and AICD. 8,53 Once the concentration of stimulatory cytokines decreases, prosurvival signals diminish and the levels of Bcl-2, Bcl-x L , and Mcl-1 rapidly decrease, whereas the levels of Bim expression are maintained high.…”

The Contraction Phase of Virus-Specific CD8+ T Cells Is Unaffected by a Pan-Caspase Inhibitor

“…Bim, a pro-apoptotic member of the Bcl-2-family, is a candidate mediator of caspase-independent T cell death (67). Bim-deficient activated T cells are resistant to PCD (31), and Bim has been implicated in both AICD (68) and ACAD (69). Recent data indicate that Bim is crucial for the contraction of herpes simplex virus-specific CD8 ϩ T cells (70).…”

“…In brief, cells from blood, lymph nodes, or spleens of LCMV-infected or naive mice were isolated as described above, then were incubated in round-bottom 96-well plates at 37°C, 5% CO 2 , for 5-7 h in the presence or absence of peptide in RPMI 1640 (containing 5-10% FBS, 100 M 2-ME, L-glutamine, and antibiotics). The peptides, used at a final concentration of 1-2 g/ml, represent dominant and subdominant CD8 ϩ T cell epitopes from LCMV: NP 118 [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] and NP 309 -328 (both H-2A b ). Brefeldin A (Sigma) was added to a final concentration of 5 g/ml.…”

The role of apoptosis in the development and function of T lymphocytes

“…Bax -/-Bak -/-T cells are highly resistant to multiple cell death stimuli including cytokine deprivation [36]. Furthermore, in human T cells, Bim expression can be induced by TCR signaling [199]. Bim-deficient T cells are resistant to cytokine deprivation [134] and are defective in the CD8 + contraction phase in herpes simplex virus infection [200,201].…”