biostudies-literatureXu HHoward Hughes Medical InstituteNational Institutes of HealthCancer Research InstituteHelen and Martin Kimmel Center for Biology and Medicinee20210777https://www.ebi.ac.uk/biostudies/studies/S-EPMC8421263biostudies-literatureUnknown218(11)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, theThe Journal of experimental medicineArkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation.PMC84212632R01AI080885Raghavan VNguyen HHEpiskopou VLittman DRWu LMesa KRXu HfalseArkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation.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, the2021-01-01T00:00:00Z2021 Nov2025-04-05T14:05:25.584Z2025-04-05T14:05:25.584ZS-EPMC84212633447319710.1084/jem.20210777