Stable human regulatory T cells switch to glycolysis following TNF receptor 2 costimulation
Stable human regulatory T cells switch to glycolysis following TNF receptor 2 costimulation
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DOI：
10.1038/s42255-020-00271-w
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发表时间：
2020-10-01
影响因子：
20.8
通讯作者：
Borst, Jannie
中科院分区：
文献类型：
--
作者：
de Kivit, Sander;Mensink, Mark;Borst, Jannie
激活后，常规T细胞经历mtor驱动的糖酵解开关。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，我们证明了人类胸腺来源的T-reg （tT(reg)）细胞在肿瘤坏死因子受体2 （TNFR2）共刺激下可以成为糖酵解细胞。这种共刺激在cd3激活的tT（reg）细胞中增加增殖并诱导糖酵解开关，但在T-conv细胞中没有。cd3 - tnfr2激活的tT（reg）细胞中的糖酵解是由pi3激酶- mtor信号驱动的，并支持tT（reg）细胞的身份和抑制功能。与糖酵解T-conv细胞相比，糖酵解t （reg）细胞不显示净乳酸分泌，并将葡萄糖衍生的碳输送到三羧酸循环中。体外鉴定血源性TNFR2(hi)CD4(+)CD25(hi)CD127（lo）效应T细胞，FOXP3(+)IKZF2(+)，显示葡萄糖消耗和细胞内乳酸水平增加，从而确定它们是糖酵解tT（reg）细胞。我们的研究将人类tT（reg）细胞的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。
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.