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

By Min Peng, Na Yin, S. Chhangawala, Ke Xu, Christina S. Leslie, Ming O. Li. Science, 2016

723 citations recorded by the source corpus.

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 Immunological T cell effector functions are promoted by metabolic activity–modifying levels of histone acetylation. 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.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/a826adf3af71f024f92f158523a23f46e83e44c8

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In Cancer Research

1. Erika L. Pearce
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In Immunology

1. N. Restifo
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Citations in the corpus

• Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism (2018, background): “Increased cytosolic acetyl-CoA levels can modulate histone acetylation and can regulate IFNg expression (Peng et al., 2016), and a-KG can play an important role in histone and DNA methylation.”
• Metabolic Instruction of Immunity (2017, neutral): “In a separate report, CD4 T cells deficient in LDHA expression had defects in IFN-γ production, which stemmed from widespread lack of acetylation of the Ifng locus (Peng et al., 2016).”
• Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “acetylation of the Ifng promoter and enhancer regions (77).”