Oncotarget

Research Papers:

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

Mathilde J.H. Girard-Madoux, Juliane L. Ober-Blöbaum, Léa M.M. Costes, Junda M. Kel, Dicky J. Lindenbergh-Kortleve, Inge Brouwers-Haspels, Astrid P. Heikema, Janneke N. Samsom and Björn E. Clausen _

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Oncotarget. 2016; 7:32015-32030. https://doi.org/10.18632/oncotarget.8337

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Abstract

Mathilde J.H. Girard-Madoux1,2, Juliane L. Ober-Blöbaum1,2, Léa M.M. Costes3, Junda M. Kel1, Dicky J. Lindenbergh-Kortleve3, Inge Brouwers-Haspels1, Astrid P. Heikema4, Janneke N. Samsom3,*, Björn E. Clausen1,2,*

1Department of Immunology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands

2Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

3Department of Pediatric Gastroenterology, Erasmus MC, University Medical Center, 3015 GE Rotterdam, Netherlands

4Department 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 (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.


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