Stable human regulatory T cells switch to glycolysis following TNF receptor 2 costimulation.

Following activation, conventional T (T _conv ) cells undergo an mTOR-driven glycolytic switch. Regulatory T (T _reg ) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymus-derived T _reg (tT _reg ) 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 tT _reg cells, but not in T _conv cells. Glycolysis in CD3-TNFR2-activated tT _reg cells is driven by PI3-kinase-mTOR signalling and supports tT _reg cell identity and suppressive function. In contrast to glycolytic T _conv cells, glycolytic tT _reg cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2 ^hi CD4 ⁺ CD25 ^hi CD127 ^lo effector T cells, which were FOXP3 ⁺ IKZF2 ⁺ , revealed an increase in glucose consumption and intracellular lactate levels, thus identifying them as glycolytic tT _reg cells. Our study links TNFR2 costimulation in human tT _reg cells to metabolic remodelling, providing an additional avenue for drug targeting.