Liang Wei, Geng Ming, Rao Wenzhuo, Li Kang, Zhu Yating, Zheng Yuying, Wei Xiumei, Yang Jialong
State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
Cell Mol Life Sci. 2025 May 28;82(1):218. doi: 10.1007/s00018-025-05746-1.
The integration of metabolic programs with T cell signaling establishes a molecular foundation for immune metabolism. As a key metabolic regulator, GSK3β's activity is dynamically modulated by phosphorylation at Ser9 and Tyr216. However, the contribution of these phosphorylation sites on metabolism-driven T cell response remains unclear. Using tilapia and mouse models, we investigated the regulation of GSK3β on T cell metabolism and its evolutionary variation. In tilapia, T cell activation induces GSK3β signaling, linking to both glycolysis and oxidative phosphorylation (OXPHOS). Tyr216 phosphorylation preferentially promotes glycolysis, facilitating T cell activation, proliferation, and antibacterial immunity; while inhibition of Ser9 phosphorylation specifically enhances OXPHOS to sustain T cell responses. Differently, Tyr216 phosphorylation supports both glycolysis and OXPHOS in mouse, ensuring CD4 T and CD8 T cell activation, proliferation, and cytokine production. Although Ser9 phosphorylation controls OXPHOS, its inhibition impairs rather than enhances OXPHOS and CD4 T cell responses in mouse. We thus revealed a previously unknown mechanism underlying T cell metabolism and proposed that, through evolution, GSK3β has restructured the regulatory strategy, enabling bidirectional control of T cell metabolism and immunity in mammals and enhancing the flexibility of the adaptive immune system.
代谢程序与T细胞信号传导的整合为免疫代谢奠定了分子基础。作为关键的代谢调节因子，糖原合酶激酶3β（GSK3β）的活性通过丝氨酸9（Ser9）和酪氨酸216（Tyr216）位点的磷酸化而受到动态调节。然而，这些磷酸化位点对代谢驱动的T细胞反应的贡献仍不清楚。我们利用罗非鱼和小鼠模型，研究了GSK3β对T细胞代谢的调控及其进化变异。在罗非鱼中，T细胞活化诱导GSK3β信号传导，与糖酵解和氧化磷酸化（OXPHOS）均相关联。酪氨酸216位点的磷酸化优先促进糖酵解，有利于T细胞活化、增殖和抗菌免疫；而抑制丝氨酸9位点的磷酸化则特异性增强氧化磷酸化以维持T细胞反应。不同的是，酪氨酸216位点的磷酸化在小鼠中同时支持糖酵解和氧化磷酸化，确保CD4+T细胞和CD8+T细胞的活化、增殖以及细胞因子产生。虽然丝氨酸9位点的磷酸化控制氧化磷酸化，但在小鼠中抑制该位点的磷酸化会损害而非增强氧化磷酸化和CD4+T细胞反应。因此，我们揭示了T细胞代谢背后一种前所未知的机制，并提出，通过进化，GSK3β重塑了调控策略，在哺乳动物中实现了对T细胞代谢和免疫的双向控制，并增强了适应性免疫系统的灵活性。
