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  3. Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses

Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses

  • Immunity. 2019 Oct 15;51(4):696-708.e9. doi: 10.1016/j.immuni.2019.09.004.
Heping Xu 1,  Jiarui Ding 2,  Caroline B M Porter 2,  Antonia Wallrapp 3,  Marcin Tabaka 2,  Sai Ma 2,  Shujie Fu 4,  Xuanxuan Guo 4,  Samantha J Riesenfeld 2,  Chienwen Su 5,  Danielle Dionne 2,  Lan T Nguyen 2,  Ariel Lefkovith 2,  Orr Ashenberg 2,  Patrick R Burkett 3,  Hai Ning Shi 5,  Orit Rozenblatt-Rosen 2,  Daniel B Graham 6,  Vijay K Kuchroo 7,  Aviv Regev 8,  Ramnik J Xavier 9
Affiliations

Affiliations

  • 1 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China; Laboratory of Systems Immunology, Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang Province, China. Electronic address: [email protected].
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3 Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02114, USA.
  • 4 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China; Laboratory of Systems Immunology, Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang Province, China.
  • 5 Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • 6 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02114, USA.
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02114, USA.
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: [email protected].
  • 9 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
PMID: 31618654 DOI: 10.1016/j.immuni.2019.09.004
Abstract

Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated Neuronal Signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.

Keywords

CGRP; allergic inflammation; batch effect correction; intestinal immune cell atlas; neuro-immune interaction; neuropeptides; scRNA-seq; single cell genomics; topic model; type 2 innate lymphoid cells.

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