{"doi":"10.1101/461228","title":"Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors","abstract":"Psoriasis pathology is driven by the type 3 cytokines IL-17 and Il-22, but little is understood about the dynamics that initiate alterations in tissue homeostasis. Here, we use mouse models, single-cell RNA-seq (scRNA-seq), computational inference and cell lineage mapping to show that psoriasis induction reconfigures the functionality of skin-resident ILCs to initiate disease. Tissue-resident ILCs amplified an initial IL-23 trigger and were sufficient, without circulatory ILCs, to drive pathology, indicating that ILC tissue remodeling initiates psoriasis. Skin ILCs expressed type 2 cytokines IL-5 and IL-13 in steady state, but were epigenetically poised to become ILC3-like cells. ScRNA-seq profiles of ILCs from psoriatic and naïve skin of wild type (WT) and Rag1 -/- mice form a dense continuum, consistent with this model of fluid ILC states. We inferred biological “topics” underlying these states and their relative importance in each cell with a generative model of latent Dirichlet allocation, showing that ILCs from untreated skin span a spectrum of states, including a naïve/quiescent-like state and one expressing the Cd74 and Il13 but little Il5 . Upon disease induction, this spectrum shifts, giving rise to a greater proportion of classical Il5- and Il13- expressing “ILC2s” and a new, mixed ILC2/ILC3-like subset, expressing Il13, Il17, and Il22 . Using these key topics, we related the cells through transitions, revealing a quiescence-ILC2-ILC3s state trajectory. We demonstrated this plasticity in vivo , combining an IL-5 fate mouse with IL-17A and IL-22 reporters, validating the transition of IL-5–producing ILC2s to IL-22– and IL-17A–producing cells during disease initiation. Thus, steady-state skin ILCs are actively repressed and cued for a plastic, type 2 response, which, upon induction, morphs into a type 3 response that drives psoriasis. This suggests a general model where specific immune activities are primed in healthy tissue, dynamically adapt to provocations, and left unchecked, drive pathological remodeling.","journal":null,"year":2018,"id":12035,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0579,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2018-11-11","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":14743,"name":"Samantha J. Riesenfeld","orcid":"0000-0001-9144-021X","position":1,"is_corresponding":false},{"id":2681,"name":"Monika S. Kowalczyk","orcid":"0000-0003-0525-9196","position":2,"is_corresponding":false},{"id":80238,"name":"María Carolina Amezcua Vesely","orcid":"0000-0001-9631-1249","position":3,"is_corresponding":false},{"id":80223,"name":"Lina Kroehling","orcid":"0000-0003-4996-7450","position":4,"is_corresponding":false},{"id":80227,"name":"Parastou Yaghoubi","orcid":null,"position":5,"is_corresponding":false},{"id":2276,"name":"Danielle Dionne","orcid":"0000-0002-8338-4323","position":6,"is_corresponding":false},{"id":80228,"name":"Abigail Jarret","orcid":"0000-0002-8864-9829","position":7,"is_corresponding":false},{"id":80224,"name":"Holly R. Steach","orcid":"0000-0003-0018-3129","position":8,"is_corresponding":false},{"id":80229,"name":"Heather M. McGee","orcid":"0000-0003-3761-5087","position":9,"is_corresponding":false},{"id":37729,"name":"Caroline B. M. Porter","orcid":"0000-0001-8294-5232","position":10,"is_corresponding":false},{"id":80230,"name":"Paula Licona-Limón","orcid":"0000-0002-7692-8900","position":11,"is_corresponding":false},{"id":80231,"name":"Will Bailis","orcid":"0000-0001-9420-6250","position":12,"is_corresponding":false},{"id":80233,"name":"Nicola Gagliani","orcid":"0000-0001-8514-1395","position":14,"is_corresponding":false},{"id":80235,"name":"Richard M. Locksley","orcid":"0000-0002-5468-6867","position":15,"is_corresponding":false},{"id":29633,"name":"Prisca Liberali","orcid":"0000-0003-0695-6081","position":16,"is_corresponding":false},{"id":80236,"name":"Richard A. Flavell","orcid":"0000-0003-4461-0778","position":17,"is_corresponding":false},{"id":80232,"name":"Ruaidhrí Jackson","orcid":"0000-0002-7002-0010","position":18,"is_corresponding":false},{"id":80219,"name":"Piotr Bielecki","orcid":"0000-0002-5609-1066","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","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":[]}