The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome

Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz, Amos TanayJames P. Di Santo, Eran Elinav*, Ido Amit

*Corresponding author for this work

Research output: Contribution to journalArticle

220 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1231-1246.e13
JournalCell
Volume166
Issue number5
DOIs
StatePublished - Aug 25 2016

Keywords

  • epigenome
  • innate lymphoid cells
  • microbiota
  • single-cell transcriptomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Gury-BenAri, M., Thaiss, C. A., Serafini, N., Winter, D. R., Giladi, A., Lara-Astiaso, D., Levy, M., Salame, T. M., Weiner, A., David, E., Shapiro, H., Dori-Bachash, M., Pevsner-Fischer, M., Lorenzo-Vivas, E., Keren-Shaul, H., Paul, F., Harmelin, A., Eberl, G., Itzkovitz, S., ... Amit, I. (2016). The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome. Cell, 166(5), 1231-1246.e13. https://doi.org/10.1016/j.cell.2016.07.043