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

SummaryThe 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.