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

TY - JOUR

T1 - Skin-resident innate lymphoid cells converge on a pathogenic effector state

AU - Bielecki, Piotr

AU - Riesenfeld, Samantha J

AU - Hütter, Jan-Christian

AU - Torlai Triglia, Elena

AU - Kowalczyk, Monika S

AU - Ricardo-Gonzalez, Roberto R

AU - Lian, Mi

AU - Amezcua Vesely, Maria C

AU - Kroehling, Lina

AU - Xu, Hao

AU - Slyper, Michal

AU - Muus, Christoph

AU - Ludwig, Leif S

AU - Christian, Elena

AU - Tao, Liming

AU - Kedaigle, Amanda J

AU - Steach, Holly R

AU - York, Autumn G

AU - Skadow, Mathias H

AU - Yaghoubi, Parastou

AU - Dionne, Danielle

AU - Jarret, Abigail

AU - McGee, Heather M

AU - Porter, Caroline B M

AU - Licona-Limón, Paula

AU - Bailis, Will

AU - Jackson, Ruaidhrí

AU - Gagliani, Nicola

AU - Gasteiger, Georg

AU - Locksley, Richard M

AU - Regev, Aviv

AU - Flavell, Richard A

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation

KW - Cell Lineage

KW - Chromatin/genetics

KW - Disease Models, Animal

KW - Female

KW - Immunity, Innate/immunology

KW - Inflammation/genetics

KW - Interleukin-23/immunology

KW - Latent Class Analysis

KW - Lymphocytes/classification

KW - Male

KW - Mice

KW - Psoriasis/genetics

KW - RNA, Small Cytoplasmic/genetics

KW - Reproducibility of Results

KW - Skin/immunology

KW - Time Factors

U2 - 10.1038/s41586-021-03188-w

DO - 10.1038/s41586-021-03188-w

M3 - SCORING: Journal article

C2 - 33536623

VL - 592

SP - 128

EP - 132

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7852

ER -