对病原体或癌症的保护性免疫由特异性抗原的原始T细胞的激活和克隆扩增调节。为了维持它们的快速增殖和效应器功能，原始T细胞通过增加有氧糖酵解水平、线粒体代谢和氧化磷酸化来切换静息代谢为具有合成代谢，以产生能量和信号分子。然而，如何通过代谢重构来推动和定义T细胞的分化仍然不清楚。我们在这里展示扩增的效应器CD8+T细胞通过线粒体酶异柠檬酸脱氢酶2（IDH2）对谷氨酰胺进行还原性羧化。值得注意的是，删除编码IDH2的基因并不影响T细胞的增殖或效应器功能，但促进内存CD8+T细胞的分化。因此，在体外制造嵌合抗原受体（CAR）T细胞时抑制IDH2会诱导内存T细胞特征并增强黑色素瘤、白血病和多发性骨髓瘤的抗肿瘤活性。机制上，抑制IDH2激活代谢途径的代偿效应，导致代谢物失衡，调节组蛋白修饰酶，维持必要内存T细胞分化的基因的染色质可及性。这些发现显示CD8+T细胞中还原性羧化对它们的效应应答和增殖并非必需，但主要产生一种代谢物模式，将CD8+T细胞在终末效应分化程序中进行表观遗传锁定。阻断这一代谢途径可以增加内存T细胞的形成，优化CAR T细胞的治疗效果。© 2023. Springer Nature Limited独家许可下作者编写。

Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.