ReportsImmunology

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

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Science  28 Oct 2016:
Vol. 354, Issue 6311, pp. 481-484
DOI: 10.1126/science.aaf6284

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Metabolic support for T cell functions

For immunological T cells, responding to infections is energetically demanding. T cells rewire their metabolism so that they rely more heavily on aerobic glycolysis. This helps them to support important effector functions such as secreting the cytokine interferon γ (IFNγ). Peng et al. now provide insight into how aerobic glycolysis promotes T cell effector function. Activated T cells express the aerobic glycolysis–supporting enzyme lactate dehydrogenase A (LDHA), allowing these cells to maintain high amounts of acetyl–coenzyme A, which in turn promotes histone acetylation and transcription of cytokines such as IFNγ. Engineered mice whose T cells lacked LDHA were protected from IFNγ-dependent pathologies that often characterize autoinflammatory diseases.

Science, this issue p. 481

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.

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