1 Scientific RepoRts | 6:26091 | DOI: 10.1038/srep26091 www.nature.com/scientificreports Balancing intestinal and systemic inlammation through cell type- speciic expression of the aryl hydrocarbon receptor repressor olga Brandstätter 1,2,* , Oliver Schanz 1,* , Julia Vorac 1,2,* , Jessica König 1 , Tetsushi Mori 3 , Toru Maruyama 3 , Markus Korkowski 2 , Thomas Haarmann-Stemmann 2 , Dorthe von Smolinski 4 , Joachim L. Schultze 5 , Josef Abel 2 , Charlotte Esser 2 , Haruko Takeyama 3 , Heike Weighardt 1,2,† & Irmgard Förster 1,2,† As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, diferent from other AhR target genes. Whereas AhRR antagonizes the anti-inlammatory function of the AhR in the context of systemic endotoxin shock, AhR and AhRR act in concert to dampen intestinal inlammation. Speciically, AhRR contributes to the maintenance of colonic intraepithelial lymphocytes and prevents excessive IL-1β production and Th17/Tc17 diferentiation. In contrast, the AhRR enhances IFN-γ-production by efector T cells in the inlamed gut. Our indings highlight the physiologic importance of cell-type speciic balancing of AhR/AhRR expression in response to microbial, nutritional and other environmental stimuli. he aryl hydrocarbon receptor (AhR) is well known as a ligand-activated transcription factor important for xenobiotic metabolism in the liver and other organs. However, AhR not only acts as a sensor for environmental toxins but also for physiological low molecular weight ligands, such as tryptophan derived photoproducts or dietary components 1–3 . In addition to its important role in xenobiotic metabolism, the AhR signaling pathway also exerts essential regulatory functions in immunity 4,5 . AhR activation can directly inluence the h17/Treg balance, facilitating either the generation of Treg or that of h17 cells depending on the disease model, tissue context and type of AhR ligand 6–13 . Direct ligand-dependent activation of the AhR in vitro was shown to enhance h17 diferentiation 6,11,14–17 , whereas AhR activation in vivo oten has an anti-inlammatory efect 18–21 . In line with this anti-inlammatory function, AhR-deicient mice are hypersensitive to LPS-induced shock 22,23 , inlammatory bowel disease 8,24,25 and Citrobacter rodentium infection 8,26,27 . Furthermore, AhR activation was shown to protect from DSS-induced colitis 9,19,20,28 . To maintain appropriate barrier immunity, the AhR is critically involved in the development and function of innate lymphoid cells (ILC)-3 in the intestine, in particular IL-22-producing NKp46 + RORγt + ILC3 8,26,27 . he AhR is essential for c-kit-dependent intraepithelial γδ T cell expansion in small intestine and colon 24 , as well as skin 29 . Furthermore, activation of the AhR was shown to inluence the diferentiation and activation of DC in vitro and in vivo 30–32 . 1 immunology and environment, Life and Medical Sciences (LiMeS) institute, University of Bonn, carl- troll-Straße 31, 53115 Bonn, Germany. 2 IUF-Leibniz Research Institute for Environmental Medicine gGmbH, Auf´m Hennekamp 50, 40225 Düsseldorf, Germany. 3 Center for Advanced Biomedical Sciences (TWIns), Waseda University, 2-2, Wakamatsu-cho, Shinjuku-ku, 162-8480, Tokyo, Japan. 4 Institut für Tierpathologie der FU Berlin, Robert von Ostertag Strasse 15, 14163 Berlin. 5 Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Straße 31, 53115 Bonn, Germany. * These authors contributed equally to this work. † These authors jointly supervised this work. Correspondence and requests for materials should be addressed to H.W. (email: Heike.Weighardt@uni-bonn.de) or I.F. (email: irmgard.foerster@uni-bonn.de) received: 23 December 2015 Accepted: 25 April 2016 Published: 17 May 2016 OPEN