Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation

TGF-beta 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-beta signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), an E3 ubiquitin ligase that mediates TGF-beta signaling during development. Inactivation of Arkadia in CD4(+) T cells resulted in impaired Treg cell differentiation in vitro and loss of RORyt(+)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-beta signaling modules governing Th17 and iTreg cell differentiation programs that could be targeted to selectively modulate T cell functions.

Automated summary

TGF-beta signaling is crucial for differentiation of Th17 and Treg cells, with distinct requirements for downstream signaling components. Arkadia deficiency impairs Treg cell differentiation but is dispensable for Th17 cell responses. Genetic ablation of transcriptional corepressors SKI and SnoN rescues Arkadia-deficient iTreg cell differentiation.