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

Russell G. Jones, Thi Bui, Carl White, Muniswamy Madesh, Connie M. Krawczyk, Tullia Lindsten, Brian J. Hawkins, Sara Kubek, Kenneth A. Frauwirth, Y. Lynn Wang, Stuart J. Conway, H. Llewelyn Roderick, Martin D. Bootman, Hao Shen, J. Kevin Foskett, Craig B. Thompson

Research output: Contribution to journalArticle

80 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)268-280
Number of pages13
JournalImmunity
Volume27
Issue number2
DOIs
StatePublished - Aug 24 2007
Externally publishedYes

Keywords

  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Jones, R. G., Bui, T., White, C., Madesh, M., Krawczyk, C. M., Lindsten, T., Hawkins, B. J., Kubek, S., Frauwirth, K. A., Wang, Y. L., Conway, S. J., Roderick, H. L., Bootman, M. D., Shen, H., Foskett, J. K., & Thompson, C. B. (2007). The Proapoptotic Factors Bax and Bak Regulate T Cell Proliferation through Control of Endoplasmic Reticulum Ca2+ Homeostasis. Immunity, 27(2), 268-280. https://doi.org/10.1016/j.immuni.2007.05.023