Bcl-2 differentially regulates Ca²⁺ signals according to the strength of T cell receptor activation

To investigate the effect of Bcl-2 on Ca²⁺ signaling in T cells, we continuously monitored Ca²⁺ concentration in Bcl-2–positive and –negative clones of the WEHI7.2 T cell line after T cell receptor (TCR) activation by anti-CD3 antibody. In Bcl-2–negative cells, high concentrations of anti-CD3 antibody induced a transient Ca²⁺ elevation, triggering apoptosis. In contrast, low concentrations of anti-CD3 antibody induced Ca²⁺ oscillations, activating the nuclear factor of activated T cells (NFAT), a prosurvival transcription factor. Bcl-2 blocked the transient Ca²⁺ elevation induced by high anti-CD3, thereby inhibiting apoptosis, but did not inhibit Ca²⁺ oscillations and NFAT activation induced by low anti-CD3. Reduction in the level of all three inositol 1,4,5-trisphosphate (InsP₃) receptor subtypes by small interfering RNA inhibited the Ca²⁺ elevation induced by high but not low anti-CD3, suggesting that Ca²⁺ responses to high and low anti-CD3 may have different requirements for the InsP₃ receptor. Therefore, Bcl-2 selectively inhibits proapoptotic Ca²⁺ elevation induced by strong TCR activation without hindering prosurvival Ca²⁺ signals induced by weak TCR activation.