Dissemin is shutting down on January 1st, 2025

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Impact Journals, Oncotarget, 22(7), p. 32015-32030, 2016

DOI: 10.18632/oncotarget.8337

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

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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-10Ra deficient CD11c++ cells exhibited increased activation associated with enhanced IL-6 and TNFa 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.