The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady-state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α − CD11b + LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α − and CD8α + splenic DC subsets and enhances crosspresentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b + DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b + CCL17 + DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.Keywords: DCs r GM-CSF r IFN-γ receptor r IL-4 r Spleen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDCs are important sentinels of the immune system. Based on their developmental origin, surface phenotype, and mobility, DCs can be subdivided into several major subsets, such as plasmacytoid Correspondence: Prof. Irmgard Förster e-mail: irmgard.foerster@uni-bonn.deDCs, resident DCs of lymphoid organs, and migratory DC subsets, which are mainly found in nonlymphoid tissues and their local draining LN [1]. In the lamina propria of the gut and in MLN, CD103 + CD11b + DCs were identified as the major migratory DC subset with potency to induce both tolerance and immunity * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 500-510 Immunomodulation 501 [2,3]. In contrast to visceral and peripheral LN (PLN), the spleen harbors mainly lymphoid organ resident DCs with the exception of circulating plasmacytoid DCs [4]. Under inflammatory conditions monocytes are able to differentiate into mature DCs through the recognition of PAMPs in conjunction with GM-CSF (Csf-2) [5,6]. GM-CSF has been implicated in the formation of inflammatory DCs in vivo [7], and was also shown to enhance CD103 expression and the ability of CD8α + DCs to cross-present antigens to CD8 + T cells [8][9][10].Besides the classification of DC subsets on the basis of surface phenotype and migratory abilities, there is evidence that the local organ-specific microenvironment also has distinct influences on DC function even in phenotypically similar DC subsets. At the level of transcriptional profiling this has been indicated by direct comparison of...