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

Item Type:Article
Title:Skin-resident innate lymphoid cells converge on a pathogenic effector state
Creators Name:Bielecki, P. and Riesenfeld, S.J. and Hütter, J.C. and Torlai Triglia, E. and Kowalczyk, M.S. and Ricardo-Gonzalez, R.R. and Lian, M. and Amezcua Vesely, M.C. and Kroehling, L. and Xu, H. and Slyper, M. and Muus, C. and Ludwig, L.S. and Christian, E. and Tao, L. and Kedaigle, A.J. and Steach, H.R. and York, A.G. and Skadow, M.H. and Yaghoubi, P. and Dionne, D. and Jarret, A. and McGee, H.M. and Porter, C.B.M. and Licona-Limón, P. and Bailis, W. and Jackson, R. and Gagliani, N. and Gasteiger, G. and Locksley, R.M. and Regev, A. and Flavell, R.A.
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.
Keywords:Animal Disease Models, Cell Differentiation, Cell Lineage, Chromatin, Inflammation, Innate Immunity, Interleukin-23, Latent Class Analysis, Lymphocytes, Psoriasis, Reproducibility of Results, Skin, Small Cytoplasmic RNA, Time Factors, Animals, Mice
Publisher:Nature Publishing Group
Page Range:128-132
Date:1 April 2021
Official Publication:https://doi.org/10.1038/s41586-021-03188-w
PubMed:View item in PubMed

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