학술논문
Skin-resident innate lymphoid cells converge on a pathogenic effector state.
Document Type
Academic Journal
Author
Bielecki P; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. piotr.stanislaw.bielecki@gmail.com.; Celsius Therapeutics, Cambridge, MA, USA. piotr.stanislaw.bielecki@gmail.com.; Riesenfeld SJ; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. sriesenfeld@uchicago.edu.; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. sriesenfeld@uchicago.edu.; Department of Medicine, University of Chicago, Chicago, IL, USA. sriesenfeld@uchicago.edu.; Hütter JC; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Torlai Triglia E; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Kowalczyk MS; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Ricardo-Gonzalez RR; Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.; Department of Medicine, Sandler Asthma Research Center, University of California San Francisco, San Francisco, CA, USA.; Lian M; Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, Würzburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Amezcua Vesely MC; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA.; Kroehling L; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Xu H; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Slyper M; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Muus C; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.; Ludwig LS; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Christian E; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Tao L; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Kedaigle AJ; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Steach HR; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; York AG; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Skadow MH; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Yaghoubi P; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Dionne D; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Jarret A; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; McGee HM; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Sciences, La Jolla, CA, USA.; Porter CBM; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Licona-Limón P; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico.; Bailis W; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Jackson R; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Gagliani N; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.; Gasteiger G; Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, Würzburg, Germany.; Locksley RM; Department of Medicine, Sandler Asthma Research Center, University of California San Francisco, San Francisco, CA, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA.; Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. aregev@broadinstitute.org.; Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.; Genentech, South San Francisco, CA, USA. aregev@broadinstitute.org.; Flavell RA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. richard.flavell@yale.edu.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. richard.flavell@yale.edu.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Subject
Language
English
Abstract
Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines 1 . In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum-even at steady state-reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling.