The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca²⁺ homeostasis

Jones, Russell G.; Bui, Thi; White, Carl; Madesh, Muniswamy; Krawczyk, Connie M.; Lindsten, Tullia; Hawkins, Brian J.; Kubek, Sara; Frauwirth, Kenneth A.; Wang, Y. Lynn; Conway, Stuart J.; Roderick, H. Roderick; Bootman, Martin D.; Shen, Hao; Foskett, J. Kevin and Thompson, Craig B. (2007). The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca²⁺ homeostasis. Immunity, 27(2) pp. 268–280.

DOI: https://doi.org/10.1016/j.immuni.2007.05.023

Abstract

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 (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.

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