{"doi":"10.1101/2023.09.26.559434","title":"IL-2–induced Stat3 Signaling is Critical for Effector Treg Cell Programming","abstract":"Abstract Maintenance of immune homeostasis to the intestinal mictrobiota is dependent on a population of effector regulatory T (eTreg) cells that develop from microbiota-reactive induced (i)Treg cells. A cardinal feature of eTreg cells is their production of IL-10, which plays a non-redundant role in immune tolerance of commensal microbes. Here, we identify an unexpected role for IL-2-induced Stat3 signaling to program iTreg cells for eTreg cell differentiation and Il10 transcriptional competency. IL-2 proved to be both necessary and sufficient for eTreg cell development – contingent on Stat3 output of the IL-2 receptor coordinate with IL-2 signaling during early Treg cell commitment. Induction of iTreg cell programming in absence of IL-2-induced Stat3 signaling resulted in impaired eTreg cell differentiation and a failure to produce IL-10. An IL-2 mutein with reduced affinity for the IL-2Rγ (γ c ) chain was found to have blunted IL-2R Stat3 output, resulting in a deficiency of Il10 transcriptional programming that could not be fully rescued by Stat3 signaling subsequent to an initial window of iTreg cell differentiation. These findings expose a heretofore unappreciated role of IL-2 signaling that acts early to program subsequent production of IL-10 by developing eTreg cells, with broad implications for IL-2–based therapeutic interventions in immune-mediated diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":400948,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":252587,"name":"Daniel DiToro","orcid":null,"position":1,"is_corresponding":false},{"id":1042928,"name":"Duy Pham","orcid":"0000-0003-1367-6643","position":2,"is_corresponding":false},{"id":249178,"name":"Min Gao","orcid":"0000-0002-5592-9349","position":3,"is_corresponding":false},{"id":1175262,"name":"Carlene L. Zindl","orcid":"0000-0003-4841-3552","position":4,"is_corresponding":false},{"id":249177,"name":"Blake Frey","orcid":"0000-0003-3003-6904","position":5,"is_corresponding":false},{"id":249172,"name":"Stacey N. Harbour","orcid":"0000-0003-3156-7432","position":6,"is_corresponding":false},{"id":1044138,"name":"David A. Figge","orcid":"0000-0001-5737-575X","position":7,"is_corresponding":false},{"id":660066,"name":"Aidan T. Miller","orcid":"0000-0002-4931-9747","position":8,"is_corresponding":false},{"id":392207,"name":"Caleb R. Glassman","orcid":"0000-0002-3342-7989","position":9,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":10,"is_corresponding":false},{"id":249180,"name":"Robin D. Hatton","orcid":"0000-0002-4797-9899","position":11,"is_corresponding":false},{"id":249182,"name":"Casey T. Weaver","orcid":"0000-0002-2180-1793","position":12,"is_corresponding":false},{"id":1178048,"name":"Emma C. Dean","orcid":null,"position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:20:08.195423Z","pmid":"37808649","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":[]}