The Proapoptotic Factors Bax and Bak Regulate T Cell Proliferation through Control of Endoplasmic Reticulum Ca²⁺ Homeostasis

The Bcl-2-associated X protein (Bax) and Bcl-2-antagonist/killer (Bak) are essential regulators of lymphocyte apoptosis, but whether they play a role in viable T cell function remains unclear. Here, we report that T cells lacking both Bax and Bak display defects in antigen-specific proliferation because of Ca²⁺-signaling defects. Bax^-/-, Bak^-/- T cells displayed defective T cell receptor (TCR)- and inositol-1,4,5-trisphosphate (IP₃)-dependent Ca²⁺ mobilization because of altered endoplasmic reticulum (ER) Ca²⁺ regulation that was reversed by Bax's reintroduction. The ability of TCR-dependent Ca²⁺ signals to stimulate mitochondrial NADH production in excess of that utilized for ATP synthesis was dependent on Bax and Bak. Blunting of Ca²⁺-induced mitochondrial NADH elevation in the absence of Bax and Bak resulted in decreased reactive-oxygen-species production, which was required for T cell proliferation. Together, the data establish that Bax and Bak play an essential role in the control of T cell proliferation by modulating ER Ca²⁺ release.