RT Journal Article
SR Electronic
T1 Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 461228
DO 10.1101/461228
A1 Piotr Bielecki
A1 Samantha J. Riesenfeld
A1 Monika S. Kowalczyk
A1 Maria C. Amezcua Vesely
A1 Lina Kroehling
A1 Parastou Yaghoubi
A1 Danielle Dionne
A1 Abigail Jarret
A1 Holly R. Steach
A1 Heather M. McGee
A1 Caroline B. M. Porter
A1 Paula Licona-Limon
A1 Will Bailis
A1 Ruaidhri P. Jackson
A1 Nicola Gagliani
A1 Richard M. Locksley
A1 Aviv Regev
A1 Richard A. Flavell
YR 2018
UL http://biorxiv.org/content/early/2018/11/12/461228.abstract
AB 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.