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Science 336 (6086): 1321-1325

Copyright © 2012 by the American Association for the Advancement of Science

Innate Lymphoid Cells Promote Anatomical Containment of Lymphoid-Resident Commensal Bacteria

Gregory F. Sonnenberg,1 Laurel A. Monticelli,1 Theresa Alenghat,1 Thomas C. Fung,1 Natalie A. Hutnick,2 Jun Kunisawa,3,4 Naoko Shibata,3,4 Stephanie Grunberg,1 Rohini Sinha,1 Adam M. Zahm,5 Mélanie R. Tardif,6 Taheri Sathaliyawala,7 Masaru Kubota,7 Donna L. Farber,7 Ronald G. Collman,8 Abraham Shaked,9 Lynette A. Fouser,10 David B. Weiner,2 Philippe A. Tessier,6 Joshua R. Friedman,5 Hiroshi Kiyono,3,4,11 Frederic D. Bushman,1 Kyong-Mi Chang,8,12 David Artis1,13,*

Abstract: The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical containment remain unclear. Here, we show that interleukin-22 (IL-22)–producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn’s disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.

1 Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Division of Mucosal Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
4 Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Chiba 277-8562, Japan.
5 Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
6 Centre de Recherche en Infectiologie, Centre Hospitalier de l’Université Laval, Faculty of Medicine, Laval University, Quebec, Canada.
7 Department of Surgery and the Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA.
8 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
9 Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
10 Inflammation and Immunology Research Unit, Biotherapeutics Research and Development, Pfizer Worldwide R&D, Cambridge, MA 02140, USA.
11 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-0075, Japan.
12 Philadelphia VA Medical Center, Philadelphia, PA 19104, USA.
13 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: dartis{at}mail.med.upenn.edu

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