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Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors

View ORCID ProfilePiotr Bielecki, Samantha J. Riesenfeld, View ORCID ProfileMonika S. Kowalczyk, View ORCID ProfileMaria C. Amezcua Vesely, Lina Kroehling, Parastou Yaghoubi, View ORCID ProfileDanielle Dionne, View ORCID ProfileAbigail Jarret, View ORCID ProfileHolly R. Steach, View ORCID ProfileHeather M. McGee, View ORCID ProfileCaroline B. M. Porter, View ORCID ProfilePaula Licona-Limon, View ORCID ProfileWill Bailis, Ruaidhri P. Jackson, Nicola Gagliani, View ORCID ProfileRichard M. Locksley, View ORCID ProfileAviv Regev, View ORCID ProfileRichard A. Flavell
doi: https://doi.org/10.1101/461228
Piotr Bielecki
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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Samantha J. Riesenfeld
2Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge MA 02142
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Monika S. Kowalczyk
2Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge MA 02142
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  • ORCID record for Monika S. Kowalczyk
Maria C. Amezcua Vesely
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
3Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Lina Kroehling
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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Parastou Yaghoubi
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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Danielle Dionne
2Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge MA 02142
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  • ORCID record for Danielle Dionne
Abigail Jarret
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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Holly R. Steach
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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  • ORCID record for Holly R. Steach
Heather M. McGee
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
4Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Caroline B. M. Porter
2Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge MA 02142
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  • ORCID record for Caroline B. M. Porter
Paula Licona-Limon
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
5Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City 04510
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Will Bailis
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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Ruaidhri P. Jackson
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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Nicola Gagliani
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
6Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
7I. Department of Medicine, University Medical Center Hamburg-Eppendorf Hamburg-Eppendorf, 20246 Hamburg, Germany
8Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden
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Richard M. Locksley
3Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
9Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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Aviv Regev
2Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge MA 02142
3Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
10Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140
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  • For correspondence: aregev@broadinstitute.com richard.flavell@yale.edu
Richard A. Flavell
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
3Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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  • For correspondence: aregev@broadinstitute.com richard.flavell@yale.edu
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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.

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Posted November 12, 2018.
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Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors
Piotr Bielecki, Samantha J. Riesenfeld, Monika S. Kowalczyk, Maria C. Amezcua Vesely, Lina Kroehling, Parastou Yaghoubi, Danielle Dionne, Abigail Jarret, Holly R. Steach, Heather M. McGee, Caroline B. M. Porter, Paula Licona-Limon, Will Bailis, Ruaidhri P. Jackson, Nicola Gagliani, Richard M. Locksley, Aviv Regev, Richard A. Flavell
bioRxiv 461228; doi: https://doi.org/10.1101/461228
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Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors
Piotr Bielecki, Samantha J. Riesenfeld, Monika S. Kowalczyk, Maria C. Amezcua Vesely, Lina Kroehling, Parastou Yaghoubi, Danielle Dionne, Abigail Jarret, Holly R. Steach, Heather M. McGee, Caroline B. M. Porter, Paula Licona-Limon, Will Bailis, Ruaidhri P. Jackson, Nicola Gagliani, Richard M. Locksley, Aviv Regev, Richard A. Flavell
bioRxiv 461228; doi: https://doi.org/10.1101/461228

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