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

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

doi:10.1016/j.cell.2016.07.043

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

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

Research output: Contribution to journal › Article › peer-review

468 Citations (Scopus)

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 tocompare the transcriptional and epigenetic identityof small intestinal ILCs, identifying thousands ofdistinct 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 language	English
Pages (from-to)	1231-1246.e13
Number of pages	29
Journal	Cell
Volume	166
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2016.07.043
Publication status	Published - 25 Aug 2016

Funding

We thank the members of I.A.’s and E.E.’s labs for fruitful discussions, Carmit Bar-Nathan for GF mouse care taking, Elena Kartvelishvily for help with electron microscopy, Melanie Flach for technical advice, and Maayan Wigelmann for art work. C.A.T. received a Boehringer Ingelheim Fonds PhD Fellowship. E.E. is supported by Y. and R. Ungar; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the estate of J. Gitlitz; the estate of L. Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; the Adelis Foundation; J.L. and V. Schwartz; A. and G. Markovitz; A. and C. Adelson; the French National Center for Scientific Research (CNRS); D.L. Schwarz; the V.R. Schwartz Research Fellow Chair; L. Steinberg; J.N. Halpern; A. Edelheit, and by grants funded by the European Research Council; a Marie Curie Integration grant; the German-Israeli Foundation for Scientific Research and Development; the Israel Science Foundation; the Minerva Foundation; the Rising Tide Foundation; the Helmholtz Foundation; and the European Foundation for the Study of Diabetes. E.E. is the incumbent of the Rina Gudinski Career Development Chair and a senior fellow of the Canadian Institute For Advanced Research (CIFAR). I.A. is supported by the European Research Council (309788), the I-CORE for chromatin and RNA regulation, and personal grants from the Israel Science foundation (782/11) and the BLUEPRINT FP7 consortium, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Minerva Stiftung research grant, the National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193), the Israeli Ministry of Science, Technology and Space, the David and Fela Shapell Family Foundation, and the Abramson Family Center for Young Scientists. I.A. is the incumbent of the Alan and Laraine Fischer Career Development Chair.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2016.07.043

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Gury-BenAri, M., Thaiss, C. A., Serafini, N., Winter, D. R., Giladi, A., Lara Astiaso, A. D., Levy, M., Salame, T. M., Weiner, A., David, E., Shapiro, H., Dori-Bachash, M., Pevsner-Fischer, M., Lorenzo Vivas, V. 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

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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 tocompare the transcriptional and epigenetic identityof small intestinal ILCs, identifying thousands ofdistinct 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.",

author = "Meital Gury-BenAri and Thaiss, {Christoph Alexander} and Nicolas Serafini and Winter, {Deborah R} and Amir Giladi and {Lara Astiaso}, {Astiaso, David} and Maayan Levy and Salame, {Tomer Meir} and Assaf Weiner and Eyal David and Hagit Shapiro and Mally Dori-Bachash and Meirav Pevsner-Fischer and {Lorenzo Vivas}, {Vivas, Erika} and Hadas Keren-Shaul and Franziska Paul and Alon Harmelin and Gerard Eberl and Shalev Itzkovitz and Amos Tanay and {Di Santo}, {Santo, James P} and Eran Elinav and Ido Amit",

year = "2016",

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doi = "10.1016/j.cell.2016.07.043",

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Gury-BenAri, M, Thaiss, CA, Serafini, N, Winter, DR, Giladi, A, Lara Astiaso, AD, Levy, M, Salame, TM , Weiner, A , David, E , Shapiro, H, Dori-Bachash, M, Pevsner-Fischer, M, Lorenzo Vivas, VE, Keren-Shaul, H, Paul, F, Harmelin, A, Eberl, G, Itzkovitz, S , Tanay, A, Di Santo, SJP, Elinav, E & Amit, I 2016, 'The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome', Cell, vol. 166, no. 5, pp. 1231-1246.e13. https://doi.org/10.1016/j.cell.2016.07.043

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T1 - The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome

AU - Gury-BenAri, Meital

AU - Thaiss, Christoph Alexander

AU - Serafini, Nicolas

AU - Winter, Deborah R

AU - Giladi, Amir

AU - Lara Astiaso, Astiaso, David

AU - Levy, Maayan

AU - Salame, Tomer Meir

AU - Weiner, Assaf

AU - David, Eyal

AU - Shapiro, Hagit

AU - Dori-Bachash, Mally

AU - Pevsner-Fischer, Meirav

AU - Lorenzo Vivas, Vivas, Erika

AU - Keren-Shaul, Hadas

AU - Paul, Franziska

AU - Harmelin, Alon

AU - Eberl, Gerard

AU - Itzkovitz, Shalev

AU - Tanay, Amos

AU - Di Santo, Santo, James P

AU - Elinav, Eran

AU - Amit, Ido

PY - 2016/8/25

Y1 - 2016/8/25

N2 - 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 tocompare the transcriptional and epigenetic identityof small intestinal ILCs, identifying thousands ofdistinct 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.

AB - 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 tocompare the transcriptional and epigenetic identityof small intestinal ILCs, identifying thousands ofdistinct 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.

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DO - 10.1016/j.cell.2016.07.043

M3 - Article

SN - 0092-8674

VL - 166

SP - 1231-1246.e13

JO - Cell

JF - Cell

IS - 5

ER -

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

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