IL‐33 activates mTORC1 and modulates glycolytic metabolism in CD8<sup>+</sup> T cells
Yuejin Liang, Xiaofang Wang, Hui Wang, Wenjing Yang, Panpan Yi, Lynn Soong, Yingzi Cong, Jiyang Cai, Xuegong Fan, Jiaren Sun
Abstract
Abstract Interleukin (IL)‐33, a member in the IL‐1 family, plays a central role in innate and adaptive immunity; however, how IL‐33 mediates cytotoxic T‐cell regulation and the downstream signals remain elusive. In this study, we found increased mouse IL‐33 expression in CD8 + T cells following cell activation via anti‐CD3/CD28 stimulation in vitro or lymphocytic choriomeningitis virus (LCMV) infection in vivo . Our cell adoptive transfer experiment demonstrated that extracellular, but not nuclear, IL‐33 contributed to the activation and proliferation of CD8 + , but not CD4 + T effector cells in LCMV infection. Importantly, IL‐33 induced mTORC1 activation in CD8 + T cells as evidenced by increased phosphorylated S6 ribosomal protein (p‐S6) levels both in vitro and in vivo . Meanwhile, this IL‐33‐induced CD8 + T‐cell activation was suppressed by mTORC1 inhibitors. Furthermore, IL‐33 elevated glucose uptake and lactate production in CD8 + T cells in both dose‐ and time‐dependent manners. The results of glycolytic rate assay demonstrated the increased glycolytic capacity of IL‐33‐treated CD8 + T cells compared with that of control cells. Our mechanistic study further revealed the capacity of IL‐33 in promoting the expression of glucose transporter 1 (Glut1) and glycolytic enzymes via mTORC1, leading to accelerated aerobic glucose metabolism Warburg effect and increased effector T‐cell activation. Together, our data provide new insights into IL‐33‐mediated regulation of CD8 + T cells, which might be beneficial for therapeutic strategies of inflammatory and infectious diseases in the future.