瑞士洛桑大学Mathias Wenes等研究人员合作发现，还原性羧基化表观遗传指导T细胞分化。2023年9月20日，《自然》杂志在线发表了这项成果。

研究人员发现增殖的效应CD8⁺ T细胞通过线粒体酶异柠檬酸脱氢酶2（IDH2）还原羧化谷氨酰胺。值得注意的是，缺失编码IDH2的基因不会影响T细胞的增殖及其效应功能，反而会促进记忆CD8⁺ T细胞的分化。因此，在体内外制造嵌合抗原受体（CAR）T细胞的过程中抑制IDH2可诱导记忆T细胞的特征，并增强黑色素瘤、白血病和多发性骨髓瘤的抗肿瘤活性。从机理上讲，抑制IDH2会激活补偿性代谢途径，导致调节组蛋白修饰酶的代谢物失衡，从而维持记忆T细胞分化所需的基因染色质的可及性。这些研究结果表明，CD8⁺ T细胞中的还原羧基化对其效应反应和增殖来说是不可或缺的，但它主要产生一种代谢物模式，从表观遗传学上将CD8⁺ T细胞锁定为终端效应分化程序。阻断这一代谢途径可增加记忆T细胞的形成，从而优化CAR T细胞的疗效。

据了解，针对病原体或癌症的保护性免疫是通过将抗原特异性初始T细胞激活并克隆扩增为效应T细胞来实现的。为了维持其快速增殖和效应功能，初始T细胞通过增加有氧糖酵解水平，同时也通过线粒体代谢和氧化磷酸化，将其静止代谢转变为合成代谢，从而产生能量和信号分子。然而，新陈代谢的重塑如何驱动和定义T细胞的分化仍不清楚。

附：英文原文

Title: Reductive carboxylation epigenetically instructs T cell differentiation

Author: Jaccard, Alison, Wyss, Tania, Maldonado-Prez, Noelia, Rath, Jan A., Bevilacqua, Alessio, Peng, Jhan-Jie, Lepez, Anouk, Von Gunten, Christine, Franco, Fabien, Kao, Kung-Chi, Camviel, Nicolas, Martn, Francisco, Ghesquire, Bart, Migliorini, Denis, Arber, Caroline, Romero, Pedro, Ho, Ping-Chih, Wenes, Mathias

Issue&Volume: 2023-09-20

Abstract: 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 molecules1,2,3. 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.

DOI: 10.1038/s41586-023-06546-y

Source: https://www.nature.com/articles/s41586-023-06546-y