title: The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome.
abstract: Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. Here, we combine genome-wide RNA-seq, ChIP-seq, and ATAC-seq to compare the transcriptional and epigenetic identity of small intestinal ILCs, identifying thousands of distinct gene profiles and regulatory elements. Single-cell RNA-seq and flow and mass cytometry analyses reveal compartmentalization of cytokine expression and metabolic activity within the three classical ILC subtypes and highlight transcriptional states beyond the current canonical classification. In addition, using antibiotic intervention and germ-free mice, we characterize the effect of the microbiome on the ILC regulatory landscape and determine the response of ILCs to microbial colonization at the single-cell level. Together, our work characterizes the spectrum of transcriptional identities of small intestinal ILCs and describes how ILCs differentially integrate signals from the microbial microenvironment to generate phenotypic and functional plasticity.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Meital
authors.initials: M
authors.lastname: Gury-BenAri
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Thaiss
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1223 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Serafini
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Winter
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Giladi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Lara-Astiaso
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Levy
authors.affiliation: Biological Services Unit, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tomer Meir
authors.initials: TM
authors.lastname: Salame
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Weiner
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: David
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Shapiro
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Mally
authors.initials: M
authors.lastname: Dori-Bachash
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Meirav
authors.initials: M
authors.lastname: Pevsner-Fischer
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Erika
authors.initials: E
authors.lastname: Lorenzo-Vivas
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Keren-Shaul
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Franziska
authors.initials: F
authors.lastname: Paul
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.affiliation: Institut Pasteur, Microenvironment & Immunity Unit, 75724 Paris, France; INSERM U1224, 75724 Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Shalev
authors.initials: S
authors.lastname: Itzkovitz
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Tanay
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1223 Paris, France.
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: eran.elinav@weizmann.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: ido.amit@weizmann.ac.il.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
mesh_terms: D000818:Animals; D001483:Base Sequence; D002843:Chromatin / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D044127:Epigenesis, Genetic; D000069196:Gastrointestinal Microbiome; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics*; D007422:Intestines / Q000276:immunology* / Q000382:microbiology*; D008214:Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D059010:Single-Cell Analysis; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D016207:Cytokines
keywords: epigenome; innate lymphoid cells; microbiota; single-cell transcriptomics