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

TGF-β signaling is fundamental for both Th17 and regulatory T cell (Treg) differentiation. However, these cells differ in requirements for downstream signaling components, such as various SMAD effectors, for their differentiation. To further characterize the mechanisms that distinguish TGF-β signaling requirements for Th17 and Treg cell differentiation, we investigated the role of Arkadia (RNF111), a RING type E3 ubiquitin ligase known to enhance TGF-β signaling during development. We find that Arkadia mediates the differentiation of induced-Treg (iTreg) but not Th17 cells both in vitro and in vivo . Inactivation of Arkadia in CD4+ T cells resulted in impairment of Treg cell differentiation in vitro and loss of RORγt+FOXP3+ iTreg cells in the intestinal lamina propria in vivo , which increased susceptibility to microbiota-induced mucosal inflammation. Furthermore, genetic ablation of two substrates of Arkadia, the transcriptional co-repressors SKI and SnoN, rescued in vitro and in vivo iTreg cell-differentiation of Arkadia-deficient cells. These results reveal distinct TGF-β signaling modules that govern Th17 and iTreg cell differentiation programs and that could be exploited therapeutically to selectively modulate T cell subsets in pathological settings such as autoimmunity or cancer. ### Competing Interest Statement D.R.L. consults for and has equity interest in Vedanta and Immunai.