title: Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.
abstract: Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Dror S
authors.initials: DS
authors.lastname: Shouval
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Amlan
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Katelyn
authors.initials: K
authors.lastname: McCann
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Conaway
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Naresh S
authors.initials: NS
authors.lastname: Redhu
authors.affiliation: Center of Neurological Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Al Adham
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Lavoie
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Mouna
authors.initials: M
authors.lastname: Ibourk
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Deanna D
authors.initials: DD
authors.lastname: Nguyen
authors.affiliation: Laboratory of Pediatric Gastroenterology, Erasmus Medical Center-Sophia Children's Hospital, 3000 CA Rotterdam, the Netherlands; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.affiliation: Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, 3000 CA Rotterdam, the Netherlands; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Escher
authors.affiliation: Pediatric Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52661, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
authors.affiliation: Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52661, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Batia
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Rita
authors.initials: R
authors.lastname: Beier
authors.affiliation: Department of Gastroenterology, Children's National Medical Center, Washington, D.C. 20010, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Conklin
authors.affiliation: Division of Pediatric Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Christen L
authors.initials: CL
authors.lastname: Ebens
authors.affiliation: Hospital das Clínicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 30130-100, Brazil; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Fernanda G M S
authors.initials: FG
authors.lastname: Santos
authors.affiliation: Hospital das Clínicas, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 30130-100, Brazil; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Ferreira
authors.affiliation: Division of Gastroenterology, McMaster Children's Hospital, West Hamilton, Ontario L8N 3Z5, Canada; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Mary
authors.initials: M
authors.lastname: Sherlock
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Rodrigo
authors.initials: JR
authors.lastname: Mora
authors.affiliation: Center of Neurological Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS).
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115, USA; interNational Early Onset Paediatric IBD Cohort Study (NEOPICS). Electronic address: ssnapper@hms.harvard.edu.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053701:Receptors, Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C556062:IL10 protein, mouse; C499308:Rag2 protein, mouse; D053701:Receptors, Interleukin-10; D016753:Interleukin-10