Liu Yongchao, Cong Yu, Niu Yujia, Yuan Yin, Tan Fancheng, Lai Qian, Hu Yanyan, Hou Bowen, Li Jian, Lin Chunjie, Zheng Haiping, Dong Junchen, Tang Jian, Chen Qinwei, Brzostek Joanna, Zhang Xueqin, Chen Xiao Lei, Wang Hong-Rui, Gascoigne Nicholas R J, Xu Bing, Lin Shu-Hai, Fu Guo
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
Department of Hematology, First Affiliated Hospital and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.
Sci Signal. 2022 Feb 15;15(721):eabi9983. doi: 10.1126/scisignal.abi9983.
To perform their antiviral and antitumor functions, T cells must integrate signals both from the T cell receptor (TCR), which instruct the cell to remain quiescent or become activated, and from cytokines that guide cellular proliferation and differentiation. In mature CD8 T cells, Themis has been implicated in integrating TCR and cytokine signals. We investigated whether Themis plays a direct role in cytokine signaling in mature T cells. Themis was required for IL-2- and IL-15-driven CD8 T cell proliferation both in mice and in vitro. Mechanistically, we found that Themis promoted the activation of the transcription factor Stat and mechanistic target of rapamycin signaling downstream of cytokine receptors. Metabolomics and stable isotope tracing analyses revealed that Themis deficiency reduced glycolysis and serine and nucleotide biosynthesis, demonstrating a receptor-proximal requirement for Themis in triggering the metabolic changes that enable T cell proliferation. The cellular, metabolic, and biochemical defects caused by Themis deficiency were corrected in mice lacking both Themis and the phosphatase Shp1, suggesting that Themis mediates IL-2 and IL-15 receptor-proximal signaling by restraining the activity of Shp1. Together, these results not only shed light on the mechanisms of cytokine signaling but also provide new clues on manipulating T cells for clinical applications.
为了发挥其抗病毒和抗肿瘤功能，T细胞必须整合来自T细胞受体（TCR）的信号（该信号指示细胞保持静止或被激活）以及来自细胞因子的信号（这些细胞因子指导细胞增殖和分化）。在成熟的CD8 T细胞中，Themis被认为参与整合TCR和细胞因子信号。我们研究了Themis在成熟T细胞的细胞因子信号传导中是否发挥直接作用。在小鼠体内和体外，IL-2和IL-15驱动的CD8 T细胞增殖都需要Themis。从机制上讲，我们发现Themis促进细胞因子受体下游转录因子Stat和雷帕霉素作用靶点信号的激活。代谢组学和稳定同位素示踪分析表明，缺乏Themis会降低糖酵解以及丝氨酸和核苷酸的生物合成，这表明在触发使T细胞增殖的代谢变化方面，Themis在受体近端是必需的。在同时缺乏Themis和磷酸酶Shp1的小鼠中，由Themis缺乏引起的细胞、代谢和生化缺陷得到了纠正，这表明Themis通过抑制Shp1的活性来介导IL-2和IL-15受体近端信号传导。总之，这些结果不仅揭示了细胞因子信号传导的机制，还为临床应用中操纵T细胞提供了新线索。
