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.

中文翻译：

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Arkadia-SKI/SnoN 信号通路差异调节 TGF-β 诱导的 iTreg 和 Th17 细胞分化

TGF-β 信号传导是 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成分的要求不同，例如 SMAD 效应器。为了进一步表征区分 Th17 和 Treg 细胞分化的 TGF-β 信号传导要求的机制，我们研究了 Arkadia (RNF111) 的作用，这是一种在发育过程中介导 TGF-β 信号传导的 E3 泛素连接酶。^{CD4 +} T 细胞中 Arkadia 的失活导致体外 Treg 细胞分化受损和 RORγt ⁺ FOXP3 ^+丢失肠道固有层中的 iTreg 细胞增加了对微生物群诱导的粘膜炎症的易感性。相比之下，Arkadia 对 Th17 细胞反应是可有可无的。此外，基因消融两种 Arkadia 底物，即转录辅助抑制因子 SKI 和 SnoN，在体外和体内挽救了Arkadia缺陷型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，这些信号模块可以靶向选择性地调节 T 细胞功能。