Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses PMID: 31618654

ADC Targets in Oncology

2026-04-10

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

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].

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.