Sáenz-Narciso Beatriz, Bell Sarah E, Matheson Louise S, Venigalla Ram K C, Turner Martin
Immunology Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
Nat Commun. 2025 May 6;16(1):4192. doi: 10.1038/s41467-025-58993-y.
RNA binding proteins (RBP) of the ZFP36 family limit the differentiation and effector functions of CD4 and CD8 T cells, but little is known of their expression or function in regulatory T (Treg) cells. By using Treg cell-restricted deletion of Zfp36 family members we identify the role of Zfp36l1 and Zfp36l2 in Treg cells to maintain immune homeostasis. Mice with Treg cells deficient in these RBP display an inflammatory phenotype with an expansion in the numbers of type-2 conventional dendritic cells, T effector cells, T follicular helper and germinal center B cells and elevated serum cytokines and immunoglobulins. In the absence of Zfp36l1 and Zfp36l2, the pool of cycling CTLA-4 in naïve Treg cells is reduced, Treg cells are less sensitive to IL-2 and IL-7 but are more sensitive to IFNγ. In mice lacking both RBP in Treg cells, the deletion of a single allele of Ifng is sufficient to ameliorate the pathology. Our results indicate that ZFP36L1 and ZFP36L2 regulate the availability of IFNγ and are required for the maintenance of Treg cell stability. Thus, ZFP36L1 and ZFP36L2 regulate multiple pathways that enable Treg cells to enforce immune homeostasis.
锌指蛋白36（ZFP36）家族的RNA结合蛋白（RBP）限制CD4和CD8 T细胞的分化及效应功能，但它们在调节性T（Treg）细胞中的表达或功能却鲜为人知。通过对Zfp36家族成员进行Treg细胞特异性敲除，我们确定了Zfp36l1和Zfp36l2在Treg细胞中维持免疫稳态的作用。缺乏这些RBP的Treg细胞的小鼠表现出炎症表型，2型常规树突状细胞、T效应细胞、T滤泡辅助细胞和生发中心B细胞数量增加，血清细胞因子和免疫球蛋白水平升高。在缺乏Zfp36l1和Zfp36l2的情况下，初始Treg细胞中循环CTLA-4的数量减少，Treg细胞对IL-2和IL-7的敏感性降低，但对IFNγ更敏感。在Treg细胞中同时缺乏这两种RBP的小鼠中，删除Ifng的一个等位基因就足以改善病理状况。我们的结果表明，ZFP36L1和ZFP36L2调节IFNγ的可用性，是维持Treg细胞稳定性所必需的。因此，ZFP36L1和ZFP36L2调节多种途径，使Treg细胞能够维持免疫稳态。
