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Ketolysis drives CD8+ T cell effector function through effects on histone acetylation
Open accessAbstract
Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)—including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)—as essential fuels supporting CD8 + T cell metabolism and effector function. βOHB directly increased CD8 + T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8 + Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo . KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8 + T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8 + T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8 + T cell effector responses.
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“In response to bacterial infection and tumor, ketone bodies enhanced the respiratory capacity and tricarboxylic acid (TCA) cycle-dependent metabolic pathways that support CD8+ T cell function.”
From SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation (2024) · cites this paper as [13]
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“β-hydroxybutyrate (β-OHB) served as a key substrate for acetyl-coenzyme A (CoA) production in CD8+ T cells and influenced their effector responses by affecting histone acetylation.13”
From SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation (2024) · cites this paper as [13]
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“β-hydroxybutyrate (β-OHB) served as a key substrate for acetyl-coenzyme A (CoA) production in CD8+ T cells and influenced their effector responses by affecting histone acetylation.13”
From SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation (2024) · cites this paper as [13]
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Metadata
- Authors
- Luda, K. M., Longo, J., Kitchen-Goosen, S. M., Duimstra, L. R., Ma, E. H., Watson, M. J., Oswald, B. M., Fu, Z., Madaj, Z., Kupai, A., Dickson, B. M., DeCamp, L. M., Dahabieh, M. S., Compton, S. E., Teis, R., Kaymak, I., Lau, K. H., Kelly, D. P., Puchalska, P., Williams, K. S., Krawczyk, C. M., Lévesque, D., Boisvert, F.-M., Sheldon, R. D., Rothbart, S. B., Crawford, P. A., & Jones, R. G.
- Affiliations
- University of Copenhagen (DK)
- Van Andel Institute (US)
- University of Pennsylvania (US)
- University of Minnesota (US)
- Université de Sherbrooke (CA)
- Corresponding author
- Jones, Russell G.
- ORCID
- Luda, Katarzyna M.
- Longo, Joseph
- Kitchen-Goosen, Susan M.
- Duimstra, Lauren R.
- Ma, Eric H.
- Watson, McLane J.
- Oswald, Brandon M.
- Fu, Zhen
- Madaj, Zachary
- Kupai, Ariana
- Dickson, Bradley M.
- DeCamp, Lisa M.
- Dahabieh, Michael S.
- Compton, Shelby E.
- Teis, Robert
- Kaymak, Irem
- Lau, Kin H.
- Kelly, Daniel P.
- Puchalska, Patrycja
- Williams, Kelsey S.
- Krawczyk, Connie M.
- Lévesque, Dominique
- Boisvert, François-Michel
- Sheldon, Ryan D.
- Rothbart, Scott B.
- Crawford, Peter A.
- Jones, Russell G.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2023-09
- Volume
- 56
- Issue
- 9
- Pages
- 2021-2035.e8
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC10528215
- OpenAlex
- W4385351665
- Cited by
- 140
- References
- 82
- Citations by year
- 2026: 44 · 2025: 52 · 2024: 38 · 2023: 6
- FWCI
- 15.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG069781)
- Canadian Institutes of Health Research (281824, 181903_1)
- Fonds de Recherche du Québec - Santé (281824)
- National Institute on Aging (AG069781, R01AG069781)
- National Heart, Lung, and Blood Institute (R01HL128349, R01HL151345)
- National Cancer Institute (T32CA251066)
- National Institute of General Medical Sciences (R35GM124736)
- National Institute of Allergy and Infectious Diseases (R21AI153997, R01AI165722)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK091538, R01DK091538)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- ketolysis, ketone bodies, beta-hydroxybutyrate, acetoacetate, CD8+ T cells, T cell metabolism, histone acetylation, acetyl-CoA, TCA cycle, cytokine production, cytotoxicity, bacterial infection, antitumor immunity, epigenetic regulation, glucose metabolism
- MeSH terms
- Acetylation, Animals, Histones, Ketone Bodies, CD8-Positive T-Lymphocytes, 3-Hydroxybutyric Acid, Mice
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