The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation

SummaryTo 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.

Graphical AbstractFigure optionsDownload high-quality image (334 K)Download as PowerPoint slideHighlights
► 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