The Proapoptotic Factors Bax and Bak Regulate T Cell Proliferation through Control of Endoplasmic Reticulum Ca2+ Homeostasis
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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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Restoring Ca2+ signals in Bax/Bak-null T cells restores mitochondrial ROS production and T cell proliferation.
“Restoring Ca2+ signals in Bax/Bak-null T cells restores mitochondrial ROS production and T cell proliferation (33).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [33]
T cells lacking Bax and Bak exhibit reduced Ca2+-dependent mitochondrial ROS production and T cell proliferation after TCR stimulation.
“T cells lacking the apoptosis regulators Bax and Bak, which display defects in intracellular Ca2+ homeostasis, exhibit reduced Ca2+-dependent mitochondrial ROS production and T cell proliferation after TCR stimulation (33).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [33]
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Exploiting the Bioenergetics of Disease-Causing Lymphocytes for Selective Immunomodulation.
Wahl, D. R. (2012) · Deep Blue (University of Michigan)
- Authors
- 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.
- Affiliations
- University of Pennsylvania (US)
- University of Maryland, College Park (US)
- Cornell University (US)
- Babraham Institute (GB)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 27
- Issue
- 2
- Pages
- 268-280
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2714273
- OpenAlex
- W2090734911
- Cited by
- 109
- References
- 46
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 1 · 2016: 2 · 2015: 5 · 2014: 7 · 2013: 12 · 2012: 11
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Open Research Online (The Open University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- Cancer Research Institute
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BBS/E/B/0000C116, BBS/E/B/00001116, BBS/E/B/0000H110)
- National Cancer Institute (R01CA099179)
- National Institute of General Medical Sciences (R01GM056328)
- Abramson Family Cancer Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Bax, Bak, Bcl-2 family proteins, T cell proliferation, endoplasmic reticulum calcium homeostasis, calcium signaling, T cell receptor signaling, inositol trisphosphate, mitochondrial NADH, reactive oxygen species, apoptosis, T cell function
- MeSH terms
- Adenosine Triphosphate, Animals, Calcium, Endoplasmic Reticulum, Energy Metabolism, Homeostasis, Mice, Mutant Strains, Mitochondria, NAD, Receptors, Antigen, T-Cell, T-Lymphocytes, Inositol 1,4,5-Trisphosphate, Apoptosis, Reactive Oxygen Species, Calcium Signaling, Cell Proliferation, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice
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