Following activation, conventional T (Tconv) cells undergo an mTOR-driven glycolytic switch. Regulatory T (Treg) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived Treg (tTreg) cells can become glycolytic in response to tumour necrosis factor receptor 2 (TNFR2) costimulation. This costimulus increases proliferation and induces a glycolytic switch in CD3-activated tTreg cells, but not in Tconv cells. Glycolysis in CD3-TNFR2-activated tTreg cells is driven by PI3-kinase-mTOR signalling and supports tTreg cell identity and suppressive function. In contrast to glycolytic Tconv cells, glycolytic tTreg cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2hiCD4+CD25hiCD127lo effector T cells, which were FOXP3+IKZF2+, revealed an increase in glucose consumption and intracellular lactate levels, thus identifying them as glycolytic tTreg cells. Our study links TNFR2 costimulation in human tTreg cells to metabolic remodelling, providing an additional avenue for drug targeting.

Original languageEnglish
Pages (from-to)1046-1061
Number of pages16
JournalNature Metabolism
Issue number10
Publication statusPublished - Oct 2020


  • CD3 Complex/metabolism
  • Citric Acid Cycle/drug effects
  • Glucose/metabolism
  • Glycolysis/drug effects
  • Humans
  • Lactic Acid/blood
  • Metabolome
  • Phosphatidylinositol 3-Kinases/metabolism
  • RNA/chemistry
  • Receptors, Tumor Necrosis Factor, Type II/drug effects
  • Sequence Analysis, RNA
  • Signal Transduction
  • T-Lymphocytes, Regulatory/metabolism
  • TOR Serine-Threonine Kinases/metabolism


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