{"doi":"10.1172/jci174981","title":"Human intraepithelial mast cell differentiation and effector function are directed by TGF-β signaling","abstract":"Mast cells (MCs) expressing a distinctive protease phenotype (MCTs) selectively expand within the epithelium of human mucosal tissues during type 2 (T2) inflammation. While MCTs are phenotypically distinct from subepithelial MCs (MCTCs), signals driving human MCT differentiation and this subset's contribution to inflammation remain unexplored. Here, we have identified TGF-β as a key driver of the MCT transcriptome in nasal polyps. We found that short-term TGF-β signaling alters MC cell surface receptor expression and partially recapitulated the in vivo MCT transcriptome, while TGF-β signaling during MC differentiation upregulated a larger number of MCT-associated transcripts. TGF-β inhibited the hallmark MCTC proteases chymase and cathepsin G at both the transcript and protein level, allowing selective in vitro differentiation of MCTs for functional study. We identified discrete differences in effector phenotype between in vitro-derived MCTs and MCTCs, with MCTs exhibiting enhanced proinflammatory lipid mediator generation and a distinct cytokine, chemokine, and growth factor production profile in response to both innate and adaptive stimuli, recapitulating functional features of their tissue-associated counterpart MC subsets. Thus, our findings support a role for TGF-β in promoting human MCT differentiation and identified a discrete contribution of this cell type to T2 inflammation.","journal":"Journal of Clinical Investigation","year":2025,"id":515982,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9458,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1108457,"name":"Eleanor Hollers","orcid":"0000-0002-5958-3090","position":1,"is_corresponding":false},{"id":993393,"name":"Alexander Perniss","orcid":"0000-0002-3143-4931","position":2,"is_corresponding":false},{"id":955074,"name":"Tessa Ryan","orcid":"0009-0001-7568-4721","position":3,"is_corresponding":false},{"id":932303,"name":"Alanna McGill","orcid":null,"position":4,"is_corresponding":false},{"id":1062485,"name":"Jonathan Hacker","orcid":"0000-0002-7712-0719","position":5,"is_corresponding":false},{"id":452838,"name":"Regan W. Bergmark","orcid":"0000-0003-3249-4343","position":6,"is_corresponding":false},{"id":279508,"name":"Neil Bhattacharyya","orcid":"0000-0003-0000-5824","position":7,"is_corresponding":false},{"id":575964,"name":"Stella E. Lee","orcid":"0000-0001-6563-6606","position":8,"is_corresponding":false},{"id":452842,"name":"Alice Z. Maxfield","orcid":"0000-0003-2608-2094","position":9,"is_corresponding":false},{"id":452841,"name":"Rachel E. Roditi","orcid":"0000-0001-7899-6336","position":10,"is_corresponding":false},{"id":279507,"name":"Lora G. Bankova","orcid":"0000-0003-1141-1529","position":11,"is_corresponding":false},{"id":104338,"name":"Kathleen M. Buchheit","orcid":"0000-0001-5977-851X","position":12,"is_corresponding":false},{"id":104341,"name":"Tanya M. Laidlaw","orcid":"0000-0001-6709-9795","position":13,"is_corresponding":false},{"id":104339,"name":"Joshua A. Boyce","orcid":"0000-0002-2401-2351","position":14,"is_corresponding":false},{"id":104337,"name":"Daniel F. Dwyer","orcid":"0000-0001-5029-261X","position":15,"is_corresponding":false},{"id":301605,"name":"Tahereh Derakhshan","orcid":"0000-0002-8829-4415","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:48:44.647022Z","pmid":"39744949","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":[]}