Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; School of Medical Sciences, Örebro University, 702 81 Örebro, Sweden.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
Cell Rep. 2021 Nov 9;37(6):109973. doi: 10.1016/j.celrep.2021.109973.
T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4 T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4 T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4 T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.
T 细胞的激活、增殖和分化涉及代谢重编程，这是基因、蛋白质和代谢物相互作用的结果。在这里，我们旨在了解参与人类 CD4 T 细胞亚群（辅助性 T 细胞 [Th]1、Th2、Th17 和诱导性调节性 T [iTreg] 细胞）激活和功能分化的代谢途径。在这里，我们结合基因组规模的代谢建模、基因表达数据和靶向及非靶向脂质组学实验，以及体外基因敲低实验，表明人类 CD4 T 细胞在激活和功能分化过程中经历特定的代谢变化。此外，我们证实了神经酰胺和糖脂生物合成途径在 Th17 分化和效应功能中的重要性。通过体外基因敲低实验，我们证实了丝氨酸棕榈酰转移酶（SPT）在 Th17 细胞表达促炎细胞因子（白细胞介素 [IL]-17A 和 IL17F）中的必需性，SPT 是从头合成鞘脂途径的关键酶。我们的研究结果为在以 Th17/nTreg 细胞失衡为特征的疾病状态下选择性操纵 CD4 T 细胞提供了全面的资源。
