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

By Hao Xu, Lin Wu, Henry Nguyen, Kailin R. Mesa, Varsha Raghavan, Vasso Episkopou, Dan R. Littman

Posted 23 Feb 2021
bioRxiv DOI: 10.1101/2021.02.23.432519

TGF-{beta} 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-{beta} 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-{beta} 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 ROR{gamma}t+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-{beta} 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.

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