title: Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism.
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.
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Yin
authors.affiliation: 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.
authors.forename: Sagar
authors.initials: S
authors.lastname: Chhangawala
authors.affiliation: 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. lim@mskcc.org.
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000107:Acetylation; D000332:Aerobiosis; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006019:Glycolysis / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology*; D018417:Th1 Cells / Q000166:cytology* / Q000201:enzymology
chemical_list: D020413:3' Untranslated Regions; D007527:Isoenzymes; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5