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

Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunity (Impact Factor: 21.56). 09/2007; 27(2):268-80. DOI: 10.1016/j.immuni.2007.05.023
Source: PubMed


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 Ca(2+)-signaling defects. Bax(-/-), Bak(-/-) T cells displayed defective T cell receptor (TCR)- and inositol-1,4,5-trisphosphate (IP(3))-dependent Ca(2+) mobilization because of altered endoplasmic reticulum (ER) Ca(2+) regulation that was reversed by Bax's reintroduction. The ability of TCR-dependent Ca(2+) signals to stimulate mitochondrial NADH production in excess of that utilized for ATP synthesis was dependent on Bax and Bak. Blunting of Ca(2+)-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 Ca(2+) release.

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    • "Following release from the thymus, antigenic stimulation of mature T cells facilitates metabolic changes that support various bioenergetically dependent processes needed for rapid clonal expansion (9). It is proposed that T cells must shift from catabolic to anabolic metabolism in order to rapidly proliferate, likely allowing them to respond to microbial infection [(10) p. 2313]. Indeed, CD8 T cells have the capacity to divide once every 4–6 h (13), a process that is highly energy dependent. "
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    • "For one, Bax has been shown to regulate the levels of ROS in healthy neurons (Kirkland and Franklin, 2007). Bax and Bak together also regulate ER calcium homeostasis in lymphocytes (Jones et al., 2007). In addition, Bax has been observed to form foci at mitochondrial fission sites in healthy cells (Karbowski et al., 2002), and deletion of Bax and Bak alters the normal rate of mitochondrial fusion (Karbowski et al., 2006). "
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    • "l point for initiation of apoptosis in response to several stimuli , such as arachidonic acid , ceramide , and H 2 O 2 ( Scorrano et al . 2003 ) . Subsequent studies have shown , however , that ER calcium regulation is also involved in nonapoptotic functions of these proteins ( i . e . , mitochondrial energy me - tabolism and T - cell activation [ Jones et al . 2007 ] ) , suggesting that ER Ca 2þ regulation rep - resents another day - job function of these pro - teins . Such nonapoptotic functions of BCL - 2 proteins appear to be conserved as the zebrafish BCL - 2 homolog Nrz has been recently shown to control the cytoskeletal dynamics during ze - brafish development by regulating ER Ca 2þ re - lea"
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