Carbon source availability drives nutrient utilization in CD8+ T cells
Open accessAbstract
How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8 + T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8 + T cells, with lactate directly fueling the TCA cycle. In fact, CD8 + T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro , with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8 + T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo . Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8 + effector T cells.
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CD8+ T cells preferentially utilize non-glucose physiologic carbon sources as metabolic fuel.
“Also, CD8+ T cells preferentially utilize non-glucose physiologic carbon sources as metabolic fuel, and their activation and effector function are regulated by carbon availability.9”
From SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation (2024) · cites this paper as [9]
The Discussion says that CD8+ T cells preferentially oxidize physiologic carbon sources when those sources are readily available, and the Results show that supplementation increases effector-molecule production. The Results do not establish the broader claim that carbon availability regulates activation: the measured activation/effector markers were unchanged with supplementation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCD8+ T cell activation and effector function are regulated by carbon availability.
“Also, CD8+ T cells preferentially utilize non-glucose physiologic carbon sources as metabolic fuel, and their activation and effector function are regulated by carbon availability.9”
From SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation (2024) · cites this paper as [9]
The Results section, “Physiologic carbon sources influence T cell survival and effector function” (page unavailable), reports that adding physiologic carbon sources increased CD8+ T-cell effector-molecule production. It also reports no change in the measured activation/effector markers or proliferation, so the broader claim that carbon availability regulates activation is not established, although two transcription factors changed. (LLM, conf=0.88)
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Self-citationSeeing the world through the eyes of cultured cells
Tan, J., Kunzmann, G. B., Virtue, S., Cantor, J. R., & Fazakerley, D. J. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.01.027 · Cited by 6 · see citing works
Li, X., Du, G., Li, L., & Ke, P. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1253783 · Cited by 6 · see citing works
Metabolic Screening of T Lymphocytes During Activation via SEAHORSE Extracellular Flux (XF) Analysis
Gubert, G. F., Hochrein, S. M., Sinning, K., & Vaeth, M. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4414-0_17 · Cited by 5 · see citing works
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Metabolic traits of T cells and the implications in autoimmune diseases
Zhou, Y., Zhou, Y., Zhu, Q., Guo, W., & Li, C. (2026) · Autoimmunity Reviews · doi:10.1016/j.autrev.2026.103989 · Cited by 6 · see citing works
Strategies for uncovering stable isotope tracing patterns between cell populations
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Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis
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NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustionPreprint
Dahabieh, M. S., DeCamp, L. M., Oswald, B. M., Kitchen-Goosen, S. M., Fu, Z. F., Vos, M., Compton, S. E., Longo, J., Williams, K. S., Ellis, A. E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.23.600279 · Cited by 5 · see citing works
Self-citation
- Authors
- Kaymak, I., Luda, K. M., Duimstra, L. R., Ma, E. H., Longo, J., Dahabieh, M. S., Faubert, B., Oswald, B. M., Watson, M. J., Kitchen-Goosen, S. M., DeCamp, L. M., Compton, S. E., Fu, Z., DeBerardinis, R. J., Williams, K. S., Sheldon, R. D., & Jones, R. G.
- Affiliations
- Van Andel Institute (US)
- University of Copenhagen (DK)
- University of Chicago (US)
- Children's Medical Center (US)
- Corresponding author
- Jones, Russell G.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 34
- Issue
- 9
- Pages
- 1298-1311.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC10068808
- OpenAlex
- W4292111508
- Cited by
- 160
- References
- 75
- Citations by year
- 2026: 40 · 2025: 43 · 2024: 41 · 2023: 31 · 2022: 5
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- Van Andel Research Institute
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Cancer Institute Division of Cancer Prevention
- National Cancer Institute Division of Cancer Epidemiology and Genetics (R35CA22044901)
- The Paul G Allen Frontiers Group
- Howard Hughes Medical Institute
- Fonds de Recherche du Québec - Santé
- National Cancer Institute (T32CA251066-01A1)
- National Institute of Allergy and Infectious Diseases (R01AI165722)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- CD8+ T cells, effector T cells, carbon source availability, nutrient utilization, T cell metabolism, glucose metabolism, T cell activation
- MeSH terms
- Nutrients, Carbon, Glucose, CD8-Positive T-Lymphocytes, Lactic Acid
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