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.
Arkadia-SKI/SnoN signaling differentially regulates TGF-β–induced iTreg and Th17 cell differentiation
Disclosures: D.R. Littman reported personal fees from Vor Biopharma, Vedanta Biosciences, and Immunai outside the submitted work. No other disclosures were reported.
- Award Id(s): 2R01AI080885
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Hao Xu, Lin Wu, Henry H. Nguyen, Kailin R. Mesa, Varsha Raghavan, Vasso Episkopou, Dan R. Littman; Arkadia-SKI/SnoN signaling differentially regulates TGF-β–induced iTreg and Th17 cell differentiation. J Exp Med 1 November 2021; 218 (11): e20210777. doi: https://doi.org/10.1084/jem.20210777
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