IL-10 control of CD11c+ myeloid cells is essential to maintain immune homeostasis in the small and large intestine

Abstract

// Mathilde J.H. Girard-Madoux 1, 2 , Juliane L. Ober-Blöbaum 1, 2 , Léa M.M. Costes 3 , Junda M. Kel 1 , Dicky J. Lindenbergh-Kortleve 3 , Inge Brouwers-Haspels 1 , Astrid P. Heikema 4 , Janneke N. Samsom 3, * , Björn E. Clausen 1, 2, * 1 Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands 2 Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany 3 Department of Pediatric Gastroenterology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands 4 Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands * These authors have contributed equally and share senior authorship Correspondence to: Björn E. Clausen, e-mail: bclausen@uni-mainz.de Keywords: CD11c+ myeloid cells, dendritic cells, interleukin 10, small intestine, celiac disease Received: July 16, 2015      Accepted: March 04, 2016      Published: March 24, 2016 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 ( Cd11c cre Il10ra fl/fl ). In contrast to the colon, the small intestine of Cd11c cre Il10ra fl/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 Cd11c cre Il10ra fl/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.