Foxp1 is critical for the maintenance of regulatory T-cell homeostasis and suppressive function
Foxp1 is critical for the maintenance of regulatory T-cell homeostasis and suppressive function
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Foxp1 对于维持调节性 T 细胞稳态和抑制功能至关重要。
DOI：
10.1371/journal.pbio.3000270
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发表时间：
2019-05-01
期刊：
影响因子：
9.8
通讯作者：
Wang, Haikun
中科院分区：
文献类型：
--
作者：
Ren, Jiazi;Han, Lei;Wang, Haikun
调节性T（Treg）细胞在维持免疫稳态和自身耐受中起核心作用。然而，Treg细胞稳态和抑制功能的分子机制仍不完全清楚。在这里，我们报告了叉头盒（Foxp）亚家族成员Foxp 1在Treg细胞中的另一个P亚家族成员的缺失导致以静止Treg细胞为代价的活化Treg（aTreg）细胞数量增加，并且还导致Treg抑制功能受损。Foxp 1缺陷Treg细胞的小鼠随着年龄的增长而发生自发性炎症性疾病;它们在结肠炎和实验性自身免疫性脑脊髓炎（EAE）模型中也有更严重的炎症性疾病。从机制上讲，我们发现Foxp 1与Foxp 3基因座的保守非编码序列2（CNS 2）元件结合，并通过稳定Foxp 3表达来帮助维持Treg抑制功能。此外，我们发现Foxp 1和Foxp 3协调调节细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的表达水平。综上所述，我们的研究表明，Foxp 1在维持Treg细胞稳态和调节Treg抑制功能中起着关键作用。
Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.