The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation

• Published in: Immunity (Cambridge, Mass.) Vol. 35; no. 6; pp. 871 - 882
• Main Authors: Wang, Ruoning, Dillon, Christopher P., Shi, Lewis Zhichang, Milasta, Sandra, Carter, Robert, Finkelstein, David, McCormick, Laura L., Fitzgerald, Patrick, Chi, Hongbo, Munger, Joshua, Green, Douglas R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.12.2011; Elsevier Limited
• Subjects: Animals; Bioenergetics; Cell activation; Cell cycle; Cell growth; Cell proliferation; Fatty acids; Gene expression; Gene Expression Regulation; Glucose - metabolism; Glutamine; Glutamine - metabolism; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Lymphocyte Activation - genetics; Lymphocytes T; Metabolic Networks and Pathways - genetics; Metabolic pathways; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Myc protein; Nucleotides; Ornithine - metabolism; Oxidation; polyamines; Polyamines - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pyruvic acid; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TOR Serine-Threonine Kinases - metabolism; Tracers; Transcription factors; Transcriptome; Tricarboxylic acid cycle
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2011.09.021

To fulfill the bioenergetic and biosynthetic demand of proliferation, T cells reprogram their metabolic pathways from fatty acid β-oxidation and pyruvate oxidation via the TCA cycle to the glycolytic, pentose-phosphate, and glutaminolytic pathways. Two of the top-ranked candidate transcription factors potentially responsible for the activation-induced T cell metabolic transcriptome, HIF1α and Myc, were induced upon T cell activation, but only the acute deletion of Myc markedly inhibited activation-induced glycolysis and glutaminolysis in T cells. Glutamine deprivation compromised activation-induced T cell growth and proliferation, and this was partially replaced by nucleotides and polyamines, implicating glutamine as an important source for biosynthetic precursors in active T cells. Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines. Therefore, a Myc-dependent global metabolic transcriptome drives metabolic reprogramming in activated, primary T lymphocytes. This may represent a general mechanism for metabolic reprogramming under patho-physiological conditions. [Display omitted] ► T cell activation drives the transcription of a distinct set of metabolic genes ► Myc is required for activation-induced metabolic reprogramming ► HIF1 is not required for activation-induced metabolic reprogramming ► Myc-driven glutaminolysis fuels polyamine biosynthesis upon T cell activation