Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
Department of Immunology, Erasmus University Medical Center, P.O. Box 2040, 3000CA, Rotterdam, Netherlands.
Nat Commun. 2022 Apr 27;13(1):2274. doi: 10.1038/s41467-022-29979-x.
CD8 T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that establish the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8 T cells and the potency of the resulting cytotoxic lymphocytes. The RBP function in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-κB, Irf8 and Notch1 transcription factors and cytokines, including Il2. Their absence in T cells, or the adoptive transfer of small numbers of CD8 T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals controlling the speed and quality of the CD8 T cell response.
CD8 T 细胞分化为效应细胞是在抗原识别后，由 T 细胞抗原受体和共刺激分子的信号启动的。然而，建立分化时间和速度的分子机制尚不清楚。在这里，我们表明 RNA 结合蛋白 (RBP) ZFP36 和 ZFP36L1 限制了激活的幼稚 CD8 T 细胞的分化速度和由此产生的细胞毒性淋巴细胞的效力。这些 RBP 在早期和短暂的时间窗口内发挥作用，通过直接结合 NF-κB、Irf8 和 Notch1 转录因子以及细胞因子（包括 Il2）的 mRNA，强制依赖 CD28 进行完全 T 细胞激活和效应分化。在 T 细胞中缺乏这些 RBP，或过继转移数量较少的缺乏 RBP 的 CD8 T 细胞，可促进对甲型流感病毒感染的抵抗力而不引起免疫病理学。这些发现强调了 ZFP36 和 ZFP36L1 作为整合控制 CD8 T 细胞反应速度和质量的早期 T 细胞激活信号的节点。
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