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

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Science  29 Sep 2016:
DOI: 10.1126/science.aaf6284

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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 levels 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.

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