S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate
Open accessAbstract
R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that 2-hydroxyglutarate accumulates in mouse CD8+ T cells in response to T-cell receptor triggering, and accumulates to millimolar levels in physiological oxygen conditions through a hypoxia-inducible factor 1-alpha (HIF-1α)-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8+ T-cell differentiation in response to this metabolite. Modulation of histone and DNA demethylation, as well as HIF-1α stability, mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8+ T cells. Thus, S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, through a metabolic-epigenetic axis, to immune fate and function.
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In response to T-cell receptor stimulation, 2HG accumulates to millimolar levels in CD8+ T cells and enhances effector differentiation through a mechanism involving altered histone and DNA methylation.
“In response to T-cell receptor stimulation, 2HG accumulates to millimolar levels in CD8+ T cells and enhances effector differentiation through a mechanism involving altered histone and DNA methylation (202).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [202]
2-hydroxyglutarate is produced by CD8+ T lymphocytes in response to T-cell receptor triggering and environmental hypoxia, and it significantly boosts proliferation, persistence, and antitumor capacity of CD8+ T lymphocytes in vivo.
“2‐hydroxyglutarate (2‐HG) is produced by CD8+ T lymphocytes in response to T‐cell receptor triggering and environmental hypoxia, and 2‐HG significantly boosts the proliferation, persistence, and antitumor capacity of CD8+ T lymphocytes in vivo.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [132]
Cellular reprogramming elicited by D-2-HG may play a prominent role in the pathogenesis of IDH-mutant tumours.
“all suggesting that cellular reprogramming elicited by D-2-HG may play a prominent role in the pathogenesis of IDH-mutant tumours135-137.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [136]
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- Authors
- Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., Chia, G. S., Sim, J., Doedens, A., Abelanet, A., Evans, C. E., Griffiths, J. R., Poellinger, L., Goldrath, A. W., & Johnson, R. S.
- Affiliations
- University of Cambridge (GB)
- National University of Singapore (SG)
- University of California San Diego (US)
- Karolinska Institutet (SE)
- Corresponding author
- Johnson, Randall S.
- ORCID
- Venue
- Nature
- Published
- 2016-10-26
- Volume
- 540
- Issue
- 7632
- Pages
- 236-241
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5149074
- OpenAlex
- W2537440061
- Cited by
- 433
- References
- 51
- Citations by year
- 2026: 20 · 2025: 37 · 2024: 52 · 2023: 39 · 2022: 42 · 2021: 62 · 2020: 49 · 2019: 60 · 2018: 41 · 2017: 30 · 2016: 1
- FWCI
- 26.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Leukemia and Lymphoma Society
- Wellcome Trust (092738/Z/10/Z, 092738, WT092738MA)
- Swedish Cancer Foundation
- Cancer Research UK (CB4110, 11562)
- European Commission (331756)
- National Research Foundation
- National Research Foundation Singapore
- Cancerfonden
- Vetenskapsrådet
- National Institutes of Health (A1096852, A1072117)
- University of California, San Diego
- Medical Research Council
- National Medical Research Council (NMRC/CIRG/1389/2014)
- National Institute of General Medical Sciences (T32GM007240)
- National Institute of Allergy and Infectious Diseases (R01AI072117, R01AI096852)
- 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
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- (R)-2-hydroxyglutarate, CD8+ T cells, immunometabolism, T cell receptor stimulation, hypoxia, HIF-1α, 2-oxoglutarate-dependent dioxygenase, histone methylation, DNA methylation, T cell differentiation, T cell proliferation, antitumor immunity
- MeSH terms
- Animals, Hypoxia, Cell Differentiation, DNA, Glutarates, Histones, Homeostasis, Ketoglutaric Acids, Lymphocyte Activation, Lysine, Oxygen, Receptors, Antigen, T-Cell, CD8-Positive T-Lymphocytes, DNA Methylation, Dioxygenases, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Stability
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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