{"doi":"10.1172/jci.insight.193038","title":"Th17 cells with regulatory phenotype are the main IL-17F and IL-26 producers in palmoplantar pustulosis","abstract":"Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder marked by erythematous pustules and desquamation on the palms and soles. While IL-17 pathways are implicated in PPP, IL-17 blockers have shown modest efficacy, underscoring the need for a deeper understanding of IL-17 involvement. To dissect the cellular and spatial architecture of PPP, we performed single-cell RNA-Seq (scRNA-Seq) on lesional, nonlesional, and healthy acral skin to examine cellular composition, transcriptomic profiles, and cell-cell interactions. Unbiased clustering revealed 9 major cell types, including an inflammatory keratinocyte subset enriched in IL-17A/TNF signatures and marked by high IL-36G expression. Within the lymphocyte compartment, we identified a hybrid \"regTh17\" population coexpressing regulatory markers (FOXP3, CTLA4, TIGIT), IL17F, and IL26. This regTh17 subset was distinguished by elevated IL1R1 and CD39, suggesting an IL-1β-driven differentiation. Spatial analyses demonstrated significant neighborhood enrichment of regTh17 cells with IL-36G+ supraspinous keratinocytes. RegTh17 cells were the predominant source of IL-17F and IL-26 signals, whereas keratinocytes were predicted as their main receivers. We further observed regTh17 coexpressing TNFRSF4 (OX40) and TNFRSF18 (GITR) specifically at sites of IL36G+ keratinocyte interactions, implicating these pathways in amplification of the IL-17/IL-36 inflammatory loop. Together, our integrated single-cell and spatial profiling uncovers Th17 plasticity in PPP, identifies a regTh17-keratinocyte interaction, and highlights IL-17F, IL-26, OX40/OX40L, and GITR/GITRL as candidate targets for precision therapies in this challenging disease.","journal":"JCI Insight","year":2025,"id":522095,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"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":1278353,"name":"Rachael Bogle","orcid":"0000-0003-3544-3023","position":1,"is_corresponding":false},{"id":350590,"name":"Haihan Zhang","orcid":"0000-0002-5902-7289","position":2,"is_corresponding":false},{"id":12809,"name":"Xianying Xing","orcid":"0000-0003-4227-6868","position":3,"is_corresponding":false},{"id":353207,"name":"Mehrnaz Gharaee‐Kermani","orcid":"0000-0002-2177-2427","position":4,"is_corresponding":false},{"id":1393504,"name":"Madalina Raducu","orcid":null,"position":5,"is_corresponding":false},{"id":500353,"name":"Jennifer Fox","orcid":null,"position":6,"is_corresponding":false},{"id":266413,"name":"Rundong Jiang","orcid":"0000-0002-9217-0749","position":7,"is_corresponding":false},{"id":249270,"name":"Olesya Plazyo","orcid":"0000-0002-6859-7590","position":8,"is_corresponding":false},{"id":233181,"name":"Paul W. Harms","orcid":"0000-0002-0802-2883","position":9,"is_corresponding":false},{"id":261950,"name":"Mio Nakamura","orcid":"0000-0002-1367-742X","position":10,"is_corresponding":false},{"id":249269,"name":"Enze Xing","orcid":"0000-0001-9358-9368","position":11,"is_corresponding":false},{"id":1219399,"name":"Michel Gilliet","orcid":"0000-0002-4609-3762","position":12,"is_corresponding":false},{"id":233179,"name":"Allison C. Billi","orcid":"0000-0001-7115-9113","position":13,"is_corresponding":false},{"id":233184,"name":"J. Michelle Kahlenberg","orcid":"0000-0002-4006-8945","position":14,"is_corresponding":false},{"id":236685,"name":"Robert L. Modlin","orcid":"0000-0003-4720-031X","position":15,"is_corresponding":false},{"id":653536,"name":"Özge Uluçkan","orcid":"0000-0001-9468-1211","position":16,"is_corresponding":false},{"id":12819,"name":"Lam C. Tsoi","orcid":"0000-0003-1627-5722","position":17,"is_corresponding":false},{"id":12829,"name":"Jóhann E. 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