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^hiCD4⁺CD25^hiCD127^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.