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S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate

Author

Listed:
  • Petros A. Tyrakis

    (Development and Neuroscience, University of Cambridge
    Cancer Research UK, Cambridge Institute, University of Cambridge)

  • Asis Palazon

    (Development and Neuroscience, University of Cambridge)

  • David Macias

    (Development and Neuroscience, University of Cambridge)

  • Kian. L. Lee

    (Cancer Science Institute of Singapore, National University of Singapore)

  • Anthony. T. Phan

    (Molecular Biology Section, UC San Diego)

  • Pedro Veliça

    (Karolinska Institute)

  • Jia You

    (Cancer Science Institute of Singapore, National University of Singapore)

  • Grace S. Chia

    (Cancer Science Institute of Singapore, National University of Singapore)

  • Jingwei Sim

    (Development and Neuroscience, University of Cambridge)

  • Andrew Doedens

    (Molecular Biology Section, UC San Diego)

  • Alice Abelanet

    (Development and Neuroscience, University of Cambridge)

  • Colin E. Evans

    (Development and Neuroscience, University of Cambridge)

  • John R. Griffiths

    (Cancer Research UK, Cambridge Institute, University of Cambridge)

  • Lorenz Poellinger

    (Cancer Science Institute of Singapore, National University of Singapore
    Karolinska Institute)

  • Ananda W. Goldrath

    (Molecular Biology Section, UC San Diego)

  • Randall S. Johnson

    (Development and Neuroscience, University of Cambridge
    Karolinska Institute)

Abstract

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.

Suggested Citation

  • Petros A. Tyrakis & Asis Palazon & David Macias & Kian. L. Lee & Anthony. T. Phan & Pedro Veliça & Jia You & Grace S. Chia & Jingwei Sim & Andrew Doedens & Alice Abelanet & Colin E. Evans & John R. Gr, 2016. "S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate," Nature, Nature, vol. 540(7632), pages 236-241, December.
    • Handle: RePEc:nat:nature:v:540:y:2016:i:7632:d:10.1038_nature20165
    DOI: 10.1038/nature20165
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    Cited by:

    1. Jacqueline A. Turner & Malia A. Fredrickson & Marc D’Antonio & Elizabeth Katsnelson & Morgan MacBeth & Robert Gulick & Tugs-Saikhan Chimed & Martin McCarter & Angelo D’Alessandro & William A. Robinson, 2023. "Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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