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Nature. 2019 Apr;568(7752):405-409. doi: 10.1038/s41586-019-1082-x. Epub 2019 Apr 3.

Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2.

Author information

1
Division of Gastroenterology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
2
Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
3
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
4
Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA.
6
Department of Pediatrics, Division of Gastroenterology and Nutrition, Weill Cornell Medicine, Cornell University, New York, NY, USA.
7
APHM, CIML, Hôpital de la Timone, Immunologie, Marseille Immunopole, Aix Marseille University, Marseille, France.
8
Innate Pharma Research Laboratories, Innate Pharma, Marseille, France.
9
Microenvironment and Immunity Unit, Institut Pasteur, Paris, France.
10
Division of Immunology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
11
Division of Gastroenterology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. gfsonnenberg@med.cornell.edu.
12
Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. gfsonnenberg@med.cornell.edu.
13
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. gfsonnenberg@med.cornell.edu.

Abstract

Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract1-4. The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (Treg) cells4-8, and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease9. However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain Treg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce Treg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1β. Macrophages in the small intestine produce IL-1β, and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining Treg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn's disease, and this correlated with lower frequencies of Treg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1β-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.

PMID:
30944470
PMCID:
PMC6481643
[Available on 2019-10-03]
DOI:
10.1038/s41586-019-1082-x

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