CD8 T 细胞通过释放细胞毒性分子和促炎细胞因子（例如 TNF 和 IFN-γ）来杀死靶细胞。细胞因子产生的程度和持续时间由转录后调节决定，本文中的关键调节因子是RNA结合蛋白(RBP)。尽管 RBP 在调节细胞因子产生中的功能重要性已被确​​定，但 RBP 控制细胞因子产生的动力学和作用模式尚不清楚。之前，我们发现 RBP ZFP36L2 阻断了静态记忆 T 细胞中预先形成的细胞因子编码 mRNA 的翻译。在这里，我们发现 ZFP36L2 以时间依赖性方式调节细胞因子的产生。 T 细胞特异性删除 ZFP36L2 (CD4-cre) 对 T 细胞激活的早期时间点（2-6 小时）内的 T 细胞发育或细胞因子产生没有影响。相比之下，ZFP36L2 在长时间 T 细胞激活（20-48 小时）期间特异性抑制 IFN-γ 的产生。 ZFP36L2 缺陷还导致长期暴露于抗原的肿瘤浸润 T 细胞中 IFN-γ 的产生增加。从机制上讲，ZFP36L2 通过以富含 AU 的元件依赖性方式破坏 Ifng mRNA 的稳定性，在激活的后期时间点调节 IFN-γ 的产生。总之，我们的结果表明 ZFP36L2 在效应 T 细胞和记忆 T 细胞中采用不同的调节结节来调节细胞因子的产生。© 2024 作者。 《欧洲免疫学杂志》由 Wiley‐VCH GmbH 出版。

CD8+ T cells kill target cells by releasing cytotoxic molecules and proinflammatory cytokines, such as TNF and IFN-γ. The magnitude and duration of cytokine production are defined by posttranscriptional regulation, and critical regulator herein are RNA-binding proteins (RBPs). Although the functional importance of RBPs in regulating cytokine production is established, the kinetics and mode of action through which RBPs control cytokine production are not well understood. Previously, we showed that the RBP ZFP36L2 blocks the translation of preformed cytokine encoding mRNA in quiescent memory T cells. Here, we uncover that ZFP36L2 regulates cytokine production in a time-dependent manner. T cell-specific deletion of ZFP36L2 (CD4-cre) had no effect on T-cell development or cytokine production during early time points (2-6 h) of T-cell activation. In contrast, ZFP36L2 specifically dampened the production of IFN-γ during prolonged T-cell activation (20-48 h). ZFP36L2 deficiency also resulted in increased production of IFN-γ production in tumor-infiltrating T cells that are chronically exposed to antigens. Mechanistically, ZFP36L2 regulates IFN-γ production at late time points of activation by destabilizing Ifng mRNA in an AU-rich element-dependent manner. Together, our results reveal that ZFP36L2 employs different regulatory nodules in effector and memory T cells to regulate cytokine production.© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.