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

Autor: Jeremy Goc, Gregory G. Putzel, Hiroki Kabata, Judith R. Kelsen, Manish A. Shah, Endi K. Santosa, Gérard Eberl, Gregory F. Sonnenberg, Coco Chu, Kendall A. Smith, Fei Teng, Lei Zhou, Robbyn Sockolow, Robert N. Baldassano, Nicholas J. Bessman, Eric Vivier
Přispěvatelé: Cornell University [New York], University of Pennsylvania, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Innate Pharma, Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, R21DK110262 and U01AI095608), the NIAID Mucosal Immunology Studies Team (MIST), the Crohn’s and Colitis Foundation, the Searle Scholars Program, the American Asthma Foundation Scholar Award, Pilot Project Funding from the Center for Advanced Digestive Care (CADC), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F. B. Thompson/Cancer Research Institute CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative and the Jill Roberts Institute (JRI) for Research in IBD. L.Z. and J.G. are supported by fellowships from the Crohn’s and Colitis Foundation (608975 and 519428). N.J.B. is supported by a fellowship from the NIH (F32AI124517). We thank the Epigenomics Core of Weill Cornell Medicine, and all contributing members of the JRI IBD Live Cell Bank, which is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. Research in the Vivier laboratory is supported by funding form the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (TILC, grant agreement no. 694502), the Agence Nationale de la Recherche, Equipe Labellisée ‘La Ligue’, Ligue Nationale contre le Cancer, MSDAvenir, Innate Pharma and institutional grants to the CIML (INSERM, CNRS and Aix-Marseille University) and to Marseille Immunopôle. Research reported in this publication was supported by the National Center for Advancing Translational Science of the National Institute of Health, under award number UL1TR002384., European Project: 694502,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,TILC(2017), University of Pennsylvania [Philadelphia], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), HUGOT, Bérengère, Targeting Innate Lymphoid Cells - TILC - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2017-01-01 - 2021-12-31 - 694502 - VALID
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Interleukin 2
MESH: Inflammation
MESH: Intestine
Small
[SDV.IMM] Life Sciences [q-bio]/Immunology
medicine.medical_treatment
[SDV]Life Sciences [q-bio]
Inflammation
Biology
MESH: Gastrointestinal Microbiome
03 medical and health sciences
0302 clinical medicine
Immunity
MESH: Interleukin-1beta
medicine
MESH: Nod2 Signaling Adaptor Protein
MESH: Animals
MESH: Mice
Multidisciplinary
MESH: Humans
MESH: Crohn Disease
MESH: T-Lymphocytes
Regulatory
Innate lymphoid cell
Interleukin
MESH: Macrophages
MESH: Interleukin-2
Small intestine
MESH: Male
3. Good health
[SDV] Life Sciences [q-bio]
030104 developmental biology
Cytokine
medicine.anatomical_structure
MESH: Homeostasis
Immunology
[SDV.IMM]Life Sciences [q-bio]/Immunology
MESH: Antigens
MESH: Immunity
Innate
medicine.symptom
MESH: Female
Homeostasis
030215 immunology
medicine.drug
MESH: Intestines
MESH: Myeloid Differentiation Factor 88
Zdroj: Nature
Nature, 2019, 568 (7752), pp.405-409. ⟨10.1038/s41586-019-1082-x⟩
Nature, Nature Publishing Group, 2019, 568 (7752), pp.405-409. ⟨10.1038/s41586-019-1082-x⟩
ISSN: 0028-0836
1476-4687
1476-4679
DOI: 10.1038/s41586-019-1082-x⟩
Popis: International audience; Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract 1-4. The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (T reg) cells 4-8 , and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease 9. 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 T reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T reg 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 T reg 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 T reg 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. To determine whether IL-2 is constitutively required for the maintenance of T reg cells and immunological homeostasis in the intestine, we administered isotype-control or anti-IL-2 neutralizing antibodies every other day to adult mice for two weeks. Within this short time period, the neutralization of IL-2 promoted an enlargement of the spleen and mesenteric lymph nodes, and caused significant reductions of T reg cells and significant increases in the proliferation of CD4 + T cells throughout the gastrointestinal tract and associated lymphoid tissues, including the mesenteric lymph nodes, large intestine and small intestine (Extended Data Fig. 1a-g). Blockade of IL-2 resulted in significantly enhanced IFNγ production by CD4 + T cells in both the small and large intestine, as well as increased IL-17A production in the large intestine (Extended Data Fig. 1h-k). Previous studies have suggested that CD4 + T cells are the dominant cellular source of IL-2 1,2. Therefore, we generated mice with a lineage-specific deletion of IL-2 in T cells by crossing IL-2-floxed mice 10 with Lck cre mice. Lck cre Il2 f/f mice exhibited a complete loss of IL-2 protein staining in T cells, and we observed a significant reduction in the number of T reg cells, and an increase in CD4 + T cell proliferation and effector function in the mesenteric lymph nodes and large intestine (Extended Data Fig. 2a-g). By contrast, deletion of
Databáze: OpenAIRE
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