Mitochondria are required for antigen-specific t cell activation through reactive oxygen species signaling
Open accessAbstract
It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs(-/-) mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, but Uqcrfs1(-/-) T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1(-/-) T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS.
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Blockade of rotenone to the binding site of ubiquinone leads to reduced electron flow to complex III and reverse electron flow through complex I into the mitochondrial matrix, leading to increased generation of matrix mtROS.
“Blockade of rotenone to the binding site of ubiquinone leads to reduced electron flow to complex III and reverse electron flow through complex I into the mitochondrial matrix leading to increased ROS generation in this compartment, namely matrix mtROS [269,416,419,420,421].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [269]
T cells deficient for Uqcrfs1 display impaired TCR-dependent ROS production and defects in antigen-specific proliferation.
“T cells deficient for ubiquinol-cytochrome c reductase (Uqcrfs1), a component of complex III of the ETC, display impaired TCR-dependent ROS production and defects in antigen-specific proliferation (31).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [31]
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van Bruggen, J. A. C., Martens, A. W. J., Fraietta, J. A., Hofland, T., Tonino, S. H., Eldering, E., Levin, M.-D., Siska, P. J., Endstra, S., Rathmell, J. C., et al. (2019) · Blood · doi:10.1182/blood.2018885863 · Cited by 187 · see citing works
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Deficits in bioenergetics and impaired immune response in granulocytes from children with autism
Napoli, E., Wong, S., Hertz-Picciotto, I., & Giulivi, C. (2014) · Pediatrics · doi:10.1542/peds.2013-1545 · Cited by 117 · see citing works
Cancer-associated adipocytes as immunomodulators in cancer
Wu, Q., Li, B., Li, J., Sun, S., Yuan, J., & Sun, S. (2021) · Biomarker Research · doi:10.1186/s40364-020-00257-6 · Cited by 105 · see citing works
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- Authors
- Sena, L. A., Li, S., Jairaman, A., Prakriya, M., Ezponda, T., Hildeman, D. A., Wang, C.-R., Schumacker, P. T., Licht, J. D., Perlman, H., Bryce, P. J., & Chandel, N. S.
- Affiliations
- Northwestern University (US)
- University of Cincinnati (US)
- Corresponding author
- Chandel, Navdeep S.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 38
- Issue
- 2
- Pages
- 225-236
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3582741
- OpenAlex
- W1967727543
- Cited by
- 1,338
- References
- 48
- Citations by year
- 2026: 119 · 2025: 117 · 2024: 123 · 2023: 124 · 2022: 126 · 2021: 128 · 2020: 141 · 2019: 81 · 2018: 99 · 2017: 74 · 2016: 77 · 2015: 57 · 2014: 44 · 2013: 26
- FWCI
- 37.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1p01hl108795-01, 5r01ai076456-10)
- National Heart, Lung, and Blood Institute (P01-HL-108795, HL-108795, P01HL071643, T32-HL76139, R01HL035440, HL35440, T32HL076139)
- National Cancer Institute (P30CA060553)
- National Institute of Allergy and Infectious Diseases (R01-AI076456, R01AI057753, R01AI040310, R21AI092490, AI-092490)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081175)
- National Institute of Neurological Disorders and Stroke (R01NS057499, R56NS047599, NS047599, R01NS047599)
- National Institute of Environmental Health Sciences (F30ES019815)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR050250, R01AR050250, R01AR054796, AR-054796)
- National Center for Research Resources (R21RR025355, RR025355)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- mitochondrial metabolism, T cell activation, reactive oxygen species, NFAT activation, interleukin-2, antigen-specific T cell expansion, glycolysis, lymphopenia, T cell proliferation
- MeSH terms
- Animals, Female, Interleukin-2, Iron-Sulfur Proteins, Lymphocyte Activation, Lymphopenia, Mitochondria, T-Lymphocytes, Electron Transport Complex III, Signal Transduction, Gene Expression, Reactive Oxygen Species, Tumor Necrosis Factor Receptor Superfamily, Member 7, Mice, Knockout, Homeodomain Proteins, Cell Proliferation, NFATC Transcription Factors, Mice
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