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.

中文翻译：

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IL-33 激活 mTORC1 并调节 CD8+ T 细胞中的糖酵解代谢

白细胞介素 (IL)-33 是 IL-1 家族的成员，在先天性和适应性免疫中起核心作用；然而，IL-33 如何介导细胞毒性 T 细胞调节和下游信号仍然难以捉摸。在这项研究中，我们发现通过体外抗 CD3/CD28 刺激或体内淋巴细胞脉络丛脑膜炎病毒 (LCMV) 感染激活细胞后，CD8 + T 细胞中的^小鼠IL-33 表达增加。我们的细胞过继转移实验表明，在 LCMV 感染中，细胞外而非细胞核中的 IL-33 有助于 CD8 ⁺而非 CD4 ⁺ T 效应细胞的活化和增殖。^{重要的是，IL-33 在 CD8 +}中诱导 mTORC1 激活体外和体内磷酸化 S6 核糖体蛋白 (p-S6) 水平的增加证明了 T 细胞。同时，这种 IL-33 诱导的 CD8 ⁺ T 细胞活化被 mTORC1 抑制剂抑制。此外，IL-33以剂量和时间依赖性方式提高 CD8 ⁺ T 细胞中的葡萄糖摄取和乳酸产生。糖酵解速率测定的结果表明 IL-33 处理的 CD8 ^{+的糖酵解能力增加}T 细胞与对照细胞的比较。我们的机制研究进一步揭示了 IL-33 通过 mTORC1 促进葡萄糖转运蛋白 1 (Glut1) 和糖酵解酶表达的能力，从而加速有氧葡萄糖代谢 Warburg 效应和增加效应 T 细胞活化。^{总之，我们的数据为 IL-33 介导的 CD8 +} T 细胞调节提供了新的见解，这可能对未来炎症和传染病的治疗策略有益。