The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis

Immunity. 2007 Aug;27(2):268-80. doi: 10.1016/j.immuni.2007.05.023. Epub 2007 Aug 9.

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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis / immunology*
  • Calcium / metabolism
  • Calcium Signaling*
  • Cell Proliferation
  • Endoplasmic Reticulum / immunology*
  • Energy Metabolism
  • Homeostasis
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / metabolism
  • NAD / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology*
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / physiology*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / physiology*

Substances

  • Reactive Oxygen Species
  • Receptors, Antigen, T-Cell
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • NAD
  • Inositol 1,4,5-Trisphosphate
  • Adenosine Triphosphate
  • Calcium