Bcl-2 blocks deadly, persistent Ca2+ increases but allows signaling Ca2+ oscillations to proceed, according to Zhong et al. (page 127). As a result, this antiapoptotic protein can save T cells from death without interfering with other Ca2+-regulated cell functions.

Calcium has a hand in many physiological processes, including the proliferation of activated T cells. So the authors were a bit perplexed when they previously discovered that Bcl-2 inhibited IP3 receptors (IP3Rs), which release Ca2+ from the ER. But they now find that only persistent Ca2+ increases are affected by Bcl-2.

These persistent increases, or “transients,” result from high concentrations of antibodies, which activate T cell receptor (TCR) signaling and induce apoptosis. Although low antibody concentrations also activate TCRs, they lead to lasting Ca2+ oscillations that favor cell survival. These oscillations were not blocked by Bcl-2. RNAi-mediated loss of IP3Rs also did not prevent Ca2+ oscillations. Perhaps, in T cells, oscillations are IP3R-independent or require only very few of these receptors.

Bcl-2 expression in T cells is temporarily down-regulated in the thymic cortex, where positive and negative selection occur. Its loss thus allows strong TCR reactions—as caused by self-antigens—to kill the T cell. In the periphery, however, the presence of Bcl-2 might protect mature T cells that encounter a strong antigen.