Skin-resident innate lymphoid cells converge on a pathogenic effector state

Piotr Bielecki (), Samantha J. Riesenfeld (), Jan-Christian Hütter, Elena Torlai Triglia, Monika S. Kowalczyk, Roberto R. Ricardo-Gonzalez, Mi Lian, Maria C. Amezcua Vesely, Lina Kroehling, Hao Xu, Michal Slyper, Christoph Muus, Leif S. Ludwig, Elena Christian, Liming Tao, Amanda J. Kedaigle, Holly R. Steach, Autumn G. York, Mathias H. Skadow, Parastou Yaghoubi, Danielle Dionne, Abigail Jarret, Heather M. McGee, Caroline B. M. Porter, Paula Licona-Limón, Will Bailis, Ruaidhrí Jackson, Nicola Gagliani, Georg Gasteiger, Richard M. Locksley, Aviv Regev () and Richard A. Flavell ()
Additional contact information
Piotr Bielecki: Yale University School of Medicine
Samantha J. Riesenfeld: Broad Institute of MIT and Harvard
Jan-Christian Hütter: Broad Institute of MIT and Harvard
Elena Torlai Triglia: Broad Institute of MIT and Harvard
Monika S. Kowalczyk: Broad Institute of MIT and Harvard
Roberto R. Ricardo-Gonzalez: University of California San Francisco
Mi Lian: Max Planck Research Group at the Julius-Maximilians-Universität Würzburg
Maria C. Amezcua Vesely: Yale University School of Medicine
Lina Kroehling: Yale University School of Medicine
Hao Xu: Yale University School of Medicine
Michal Slyper: Broad Institute of MIT and Harvard
Christoph Muus: Broad Institute of MIT and Harvard
Leif S. Ludwig: Broad Institute of MIT and Harvard
Elena Christian: Broad Institute of MIT and Harvard
Liming Tao: Broad Institute of MIT and Harvard
Amanda J. Kedaigle: Broad Institute of MIT and Harvard
Holly R. Steach: Yale University School of Medicine
Autumn G. York: Yale University School of Medicine
Mathias H. Skadow: Yale University School of Medicine
Parastou Yaghoubi: Yale University School of Medicine
Danielle Dionne: Broad Institute of MIT and Harvard
Abigail Jarret: Yale University School of Medicine
Heather M. McGee: Yale University School of Medicine
Caroline B. M. Porter: Broad Institute of MIT and Harvard
Paula Licona-Limón: Yale University School of Medicine
Will Bailis: Yale University School of Medicine
Ruaidhrí Jackson: Yale University School of Medicine
Nicola Gagliani: Yale University School of Medicine
Georg Gasteiger: Max Planck Research Group at the Julius-Maximilians-Universität Würzburg
Richard M. Locksley: University of California San Francisco
Aviv Regev: Broad Institute of MIT and Harvard
Richard A. Flavell: Yale University School of Medicine

Nature, 2021, vol. 592, issue 7852, 128-132

Abstract: 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 cytokines1. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03188-w

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