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Science. 2016 Oct 28;354(6311):481-484. Epub 2016 Sep 29.

Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism.

Author information

1
Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
2
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Physiology Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
3
Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
4
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. lim@mskcc.org.

Abstract

Aerobic glycolysis (the Warburg effect) is a metabolic hallmark of activated T cells and has been implicated in augmenting effector T cell responses, including expression of the proinflammatory cytokine interferon-γ (IFN-γ), via 3' untranslated region (3'UTR)-mediated mechanisms. Here, we show that lactate dehydrogenase A (LDHA) is induced in activated T cells to support aerobic glycolysis but promotes IFN-γ expression independently of its 3'UTR. Instead, LDHA maintains high concentrations of acetyl-coenzyme A to enhance histone acetylation and transcription of Ifng Ablation of LDHA in T cells protects mice from immunopathology triggered by excessive IFN-γ expression or deficiency of regulatory T cells. These findings reveal an epigenetic mechanism by which aerobic glycolysis promotes effector T cell differentiation and suggest that LDHA may be targeted therapeutically in autoinflammatory diseases.

PMID:
27708054
PMCID:
PMC5539971
DOI:
10.1126/science.aaf6284
[Indexed for MEDLINE]
Free PMC Article

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