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.

激活后，常规 T (T _conv ) 细胞经历 mTOR 驱动的糖酵解转换。据报道，调节性 T (T _reg ) 细胞抑制 mTOR 途径并避免糖酵解。然而，在这里我们证明人类胸腺衍生的 T _reg (tT _reg ) 细胞可以响应肿瘤坏死因子受体 2 (TNFR2) 共刺激而变成糖酵解。这种共刺激增加增殖并在 CD3 激活的 tT _reg细胞中诱导糖酵解转换，但在 T _conv细胞中没有。CD3-TNFR2 激活的 tT _reg细胞中的糖酵解由 PI3-激酶-mTOR 信号驱动并支持 tT _reg细胞特性和抑制功能。与糖酵解 T _conv细胞相比，糖酵解 tT _reg细胞不显示净乳酸分泌并将葡萄糖衍生的碳穿梭到三羧酸循环中。血液衍生的 TNFR2 ^hi CD4 ⁺ CD25 ^hi CD127 ^lo效应 T 细胞（即 FOXP3 ⁺ IKZF2 ⁺）的离体表征揭示了葡萄糖消耗和细胞内乳酸水平的增加，因此将它们鉴定为糖酵解 tT _reg细胞。我们的研究将人类 tT _reg细胞中的 TNFR2 共刺激与代谢重塑联系起来，为药物靶向提供了额外的途径。