{"doi":"10.1101/2024.02.09.579684","title":"TL1A/DR3 signaling regulates the generation of pathogenic Th9 cells in experimental inflammatory bowel disease","abstract":"OBJECTIVE: Death receptor 3 (DR3) and its ligand tumor necrosis factor like ligand 1A (TL1A), are involved in the regulation of the balance between effector and regulatory T cells in IBD. New evidence suggests a role of IL-9-secreting Th9 cells in the pathogenesis of ulcerative colitis (UC), although the molecular pathways through which IL-9 and Th9 cells may mediate intestinal inflammation in Crohn's disease (CD) are still unclear. DESIGN: We investigated the role of DR3 signaling in the differentiation of Th9 cells in mouse models of CD-like ileitis and colitis, including SAMP1/YitFc (SAMP) mice. RESULTS: Polarized-Th9 cells with functional DR3 from SAMP WT (Th9WT) harbor a pro-inflammatory signature compared to DR3-deficient Th9 cells that were obtained from DR3-/-xSAMP mice (Th9KO). Conversely, ablation of DR3 signaling generated anti-inflammatory responses, as reflected by higher numbers of IL-10 producing cells in DR3-/-xSAMP mice. Additionally, RNA-seq and phosphoproteomic analyses showed that inflammatory pathways are significantly more activated in Th9WT than in Th9KO cells. Finally, in the T-cell adoptive transfer model, Th9KO cells were less colitogenic than Th9WT, while IL-9 blockade diminished the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in Th9 cells pathogenicity. CONCLUSION: We describe herein that a functional DR3 receptor is required for the pathogenicity of Th9 cells, thus, constituting a novel mechanism by which TL1A/DR3 signaling mediates experimental CD-like ileitis. The TL1A/DR3/Th9 pro-inflammatory pathway may offer a novel therapeutic target for patients with CD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487905,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":302399,"name":"Ludovica F. Buttó","orcid":"0000-0003-0579-2521","position":1,"is_corresponding":false},{"id":339388,"name":"Adrian Gomez-Nguyen","orcid":"0000-0002-7226-6428","position":2,"is_corresponding":false},{"id":1332772,"name":"Natalia Aladyshkina","orcid":null,"position":3,"is_corresponding":false},{"id":302400,"name":"Kristine-Ann Buela","orcid":"0000-0002-1617-4027","position":4,"is_corresponding":false},{"id":302403,"name":"Abdullah Ösme","orcid":"0000-0002-7854-3668","position":5,"is_corresponding":false},{"id":343059,"name":"Ricky Chan","orcid":null,"position":6,"is_corresponding":false},{"id":370700,"name":"Giorgos Bamias","orcid":"0000-0002-5492-5717","position":7,"is_corresponding":false},{"id":240325,"name":"Theresa T. Pizarro","orcid":"0000-0003-3163-915X","position":8,"is_corresponding":false},{"id":256167,"name":"Fabio Cominelli","orcid":"0000-0002-1571-1548","position":9,"is_corresponding":false},{"id":657446,"name":"Paola Menghini","orcid":"0000-0002-8779-088X","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:08:15.008850Z","pmid":"38405912","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":[]}