Skin-resident innate lymphoid cells converge on a pathogenic effector state
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Skin-resident innate lymphoid cells converge on a pathogenic effector state. / Bielecki, Piotr; Riesenfeld, Samantha J; Hütter, Jan-Christian; Torlai Triglia, Elena; Kowalczyk, Monika S; Ricardo-Gonzalez, Roberto R; Lian, Mi; Amezcua Vesely, Maria C; Kroehling, Lina; Xu, Hao; Slyper, Michal; Muus, Christoph; Ludwig, Leif S; Christian, Elena; Tao, Liming; Kedaigle, Amanda J; Steach, Holly R; York, Autumn G; Skadow, Mathias H; Yaghoubi, Parastou; Dionne, Danielle; Jarret, Abigail; McGee, Heather M; Porter, Caroline B M; Licona-Limón, Paula; Bailis, Will; Jackson, Ruaidhrí; Gagliani, Nicola; Gasteiger, Georg; Locksley, Richard M; Regev, Aviv; Flavell, Richard A.
In: NATURE, Vol. 592, No. 7852, 04.2021, p. 128-132.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -