title: IL-10 control of CD11c+ myeloid cells is essential to maintain immune homeostasis in the small and large intestine.
abstract: Although IL-10 promotes a regulatory phenotype of CD11c+ dendritic cells and macrophages in vitro, the role of IL-10 signaling in CD11c+ cells to maintain intestinal tolerance in vivo remains elusive. To this aim, we generated mice with a CD11c-specific deletion of the IL-10 receptor alpha (Cd11ccreIl10rafl/fl). In contrast to the colon, the small intestine of Cd11ccreIl10rafl/fl mice exhibited spontaneous crypt hyperplasia, increased numbers of intraepithelial lymphocytes and lamina propria T cells, associated with elevated levels of T cell-derived IFNγ and IL-17A. Whereas naive mucosal T-cell priming was not affected and oral tolerance to ovalbumin was intact, augmented T-cell function in the lamina propria was associated with elevated numbers of locally dividing T cells, expression of T-cell attracting chemokines and reduced T-cell apoptosis. Upon stimulation, intestinal IL-10Rα deficient CD11c+ cells exhibited increased activation associated with enhanced IL-6 and TNFα production. Following colonization with Helicobacter hepaticus Cd11ccreIl10rafl/fl mice developed severe large intestinal inflammation characterized by infiltrating T cells and increased levels of Il17a, Ifng, and Il12p40. Altogether these findings demonstrate a critical role of IL-10 signaling in CD11c+ cells to control small intestinal immune homeostasis by limiting reactivation of local memory T cells and to protect against Helicobacter hepaticus-induced colitis.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.|Institute for Molecular Medicine, University Medical Center of The Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Mathilde J H
authors.initials: MJ
authors.lastname: Girard-Madoux
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.|Institute for Molecular Medicine, University Medical Center of The Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Juliane L
authors.initials: JL
authors.lastname: Ober-Blöbaum
authors.affiliation: Department of Pediatric Gastroenterology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.
authors.forename: Léa M M
authors.initials: LM
authors.lastname: Costes
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.
authors.forename: Junda M
authors.initials: JM
authors.lastname: Kel
authors.affiliation: Department of Pediatric Gastroenterology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.
authors.forename: Dicky J
authors.initials: DJ
authors.lastname: Lindenbergh-Kortleve
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Brouwers-Haspels
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.
authors.forename: Astrid P
authors.initials: AP
authors.lastname: Heikema
authors.affiliation: Department of Pediatric Gastroenterology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands.|Institute for Molecular Medicine, University Medical Center of The Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D044923:Helicobacter hepaticus / Q000276:immunology / Q000472:pathogenicity; D006706:Homeostasis; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007420:Intestine, Large / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
chemical_list: D039521:CD11c Antigen; C000611649:IFNG protein, mouse; C556062:IL10 protein, mouse; C098680:Il17a protein, mouse; D053709:Interleukin-10 Receptor alpha Subunit; D020381:Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: CD11c+ myeloid cells; celiac disease; dendritic cells; interleukin 10; small intestine