Tran Ngoc Minh Thi, Verleng Lotte J, Schrama Ellen, Busselaar Julia, Staal Mo D, de Vries Evert, Anholts Jacqueline D H, Berkers Celia R, Borst Jannie, Zaal Esther A, de Kivit Sander
Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands.
J Immunol. 2025 Jul 1;214(7):1566-1581. doi: 10.1093/jimmun/vkaf075.
T cells undergo many metabolic changes throughout the different phases of their response in lymphoid and nonlymphoid tissues. Cell metabolism meets demands for energy and biosynthesis, particularly during cell division and effector differentiation. As costimulatory receptors, CD28 and various TNF receptor (TNFR) family members shape T-cell clonal expansion, survival and effector functions and are important clinical targets. While CD28 is acknowledged as a metabolic regulator, little is known about how TNFRs shape T-cell metabolism. We here identify TNFR family member CD27 as a metabolic regulator in activated human CD4+ T cells. In the context of CD3 signaling and CD28 costimulation, CD27 proved to regulate specific metabolic functions, as determined by metabolomics and metabolic tracer experiments. CD27 costimulation supported upregulation of glycolysis, the pentose phosphate pathway and the TCA cycle, increasing the use of glucose-derived carbon and glutamine-derived nitrogen as building blocks for de novo nucleotide synthesis. It also promoted uptake of amino acids (AAs) and modulated pathways of AA metabolism. Accordingly, CD27 costimulation boosted protein translation in CD3- and CD3/CD28-activated CD4+ T cells, which proceeded via enhanced mTOR pathway activation. Remarkably, CD27, OX40 and 4-1BB all enhanced CD3-induced mTOR signaling, but only CD27 could overrule inhibitory PD-1 signaling. CD27 costimulation increased IL-2, IFNγ and TNFα production by CD3-activated CD4+ T cells, also in presence of PD-1 signaling. Next to previously defined beneficial effects of CD27 on activated T-cell survival and CTL differentiation and Th1 effector differentiation, these data support its essential contribution to T-cell metabolism and its relevance as a therapeutic target.
T细胞在淋巴组织和非淋巴组织中的不同反应阶段会经历许多代谢变化。细胞代谢满足能量和生物合成的需求，特别是在细胞分裂和效应分化期间。作为共刺激受体，CD28和各种肿瘤坏死因子受体（TNFR）家族成员塑造T细胞克隆扩增、存活和效应功能，并且是重要的临床靶点。虽然CD28被认为是一种代谢调节因子，但关于TNFR如何塑造T细胞代谢却知之甚少。我们在此确定TNFR家族成员CD27是活化的人CD4+T细胞中的一种代谢调节因子。在CD3信号传导和CD28共刺激的背景下，代谢组学和代谢示踪实验表明，CD27可调节特定的代谢功能。CD27共刺激支持糖酵解、磷酸戊糖途径和三羧酸循环的上调，增加了将葡萄糖衍生的碳和谷氨酰胺衍生的氮用作从头合成核苷酸的原料。它还促进氨基酸（AA）的摄取并调节AA代谢途径。因此，CD27共刺激增强了CD3和CD3/CD28活化的CD4+T细胞中的蛋白质翻译，这是通过增强的mTOR途径激活来实现的。值得注意的是，CD27、OX40和4-1BB均增强了CD3诱导的mTOR信号传导，但只有CD27能够克服抑制性PD-1信号传导。即使存在PD-1信号传导，CD27共刺激也能增加CD3活化的CD4+T细胞产生白细胞介素-2、干扰素γ和肿瘤坏死因子α。除了先前定义的CD27对活化T细胞存活、细胞毒性T淋巴细胞分化和Th1效应分化的有益作用外，这些数据支持其对T细胞代谢的重要贡献及其作为治疗靶点的相关性。
