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 3 , Inge Brouwers-Haspels 1 , Astrid P. Heikema 4 , Janneke N. Samsom 3 , Björn E. Clausen 1 , 2
24 March 2016
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 creIl10ra fl/fl ). In contrast to the colon, the small intestine of Cd11c creIl10ra 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 creIl10ra 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.