Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation.
Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation.
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DOI：
10.1084/jem.20210777
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发表时间：
2021-11-01
期刊：
影响因子：
--
通讯作者：
Littman DR
中科院分区：
文献类型：
--
作者：
Xu H;Wu L;Nguyen HH;Mesa KR;Raghavan V;Episkopou V;Littman DR
TGF-β信号在Th17和Treg细胞分化中都是不可或缺的。我们发现Arkadia是一种E3泛素连接酶，作用于TGF-β信号传导，在体外和体内iTreg细胞的分化中是选择性必需的，而不是Th17细胞。TGF-β信号是Th17和调节性T （Treg）细胞分化的基础。然而，这些细胞对下游信号元件（如SMAD效应物）的需求不同。为了进一步表征Th17和Treg细胞分化对TGF-β信号传导需求的区别机制，我们研究了Arkadia （RNF111）的作用，这是一种E3泛素连接酶，在发育过程中介导TGF-β信号传导。Arkadia在CD4+ T细胞中的失活导致体外Treg细胞分化受损，肠固有层中RORγt+FOXP3+ iTreg细胞的缺失，增加了对微生物诱导的粘膜炎症的易感性。相比之下，Arkadia在Th17细胞应答中是必不可少的。此外，基因消融两种Arkadia底物，转录共抑制因子SKI和SnoN，在体外和体内都挽救了Arkadia缺陷的iTreg细胞分化。这些结果揭示了控制Th17和iTreg细胞分化程序的不同TGF-β信号模块可以选择性地调节T细胞功能。
TGF-β signaling is indispensable for both Th17 and Treg cell differentiation. We show that Arkadia, an E3 ubiquitin ligase acting in TGF-β signaling, is selectively required for the differentiation of iTreg, but not Th17, cells both in vitro and in vivo. TGF-β signaling is fundamental for both Th17 and regulatory T (Treg) cell differentiation. However, these cells differ in requirements for downstream signaling components, such as SMAD effectors. To further characterize mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-β signaling during development. Inactivation of Arkadia in CD4+ T cells resulted in impaired Treg cell differentiation in vitro and loss of RORγt+FOXP3+ iTreg cells in the intestinal lamina propria, which increased susceptibility to microbiota-induced mucosal inflammation. In contrast, Arkadia was dispensable for Th17 cell responses. Furthermore, genetic ablation of two Arkadia substrates, the transcriptional corepressors SKI and SnoN, rescued Arkadia-deficient iTreg cell differentiation both in vitro and in vivo. These results reveal distinct TGF-β signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.4
作者：
Burchill, Matthew A.;Yang, Jianying;Farrar, Michael A.
通讯作者：
Farrar, Michael A.
控制FOXP3基因座中的顺式元素对调节T细胞身份的遗传控制。
影响因子：
64.5
作者：
Feng Y;Arvey A;Chinen T;van der Veeken J;Gasteiger G;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
8
作者：
Marcelain, K;Hayman, MJ
通讯作者：
Hayman, MJ