The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis.
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.
Jones
Russell G
RG
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bui
Thi
T
White
Carl
C
Madesh
Muniswamy
M
Krawczyk
Connie M
CM
Lindsten
Tullia
T
Hawkins
Brian J
BJ
Kubek
Sara
S
Frauwirth
Kenneth A
KA
Wang
Y Lynn
YL
Conway
Stuart J
SJ
Roderick
H Llewelyn
HL
Bootman
Martin D
MD
Shen
Hao
H
Foskett
J Kevin
JK
Thompson
Craig B
CB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000276:immunology*; D004734:Energy Metabolism; D006706:Homeostasis; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology*
D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D009243:NAD; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002118:Calcium
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