{"doi":"10.1101/2021.02.23.432519","title":"Arkadia-SKI/SnoN signaling cascade differentially regulates TGF-β-induced iTreg and Th17 cell differentiation","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223324,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":273817,"name":"Lin Wu","orcid":"0000-0003-3595-2207","position":1,"is_corresponding":false},{"id":231976,"name":"Henry H. Nguyen","orcid":"0000-0002-2205-3205","position":2,"is_corresponding":false},{"id":685309,"name":"Kailin R. Mesa","orcid":"0000-0003-4452-9048","position":3,"is_corresponding":false},{"id":675338,"name":"Varsha Raghavan","orcid":"0000-0003-4182-2038","position":4,"is_corresponding":false},{"id":685310,"name":"Vasso Episkopou","orcid":"0000-0002-5443-1186","position":5,"is_corresponding":false},{"id":90201,"name":"Dan R. Littman","orcid":"0000-0002-2850-8688","position":6,"is_corresponding":false},{"id":685307,"name":"Hao Xu","orcid":"0000-0003-3286-0710","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}