title: Cytokine-dependent regulation of dendritic cell differentiation in the splenic microenvironment.
abstract: 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 cross-presentation 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.
authors.affiliation: Department of Molecular Immunology, IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany; Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Globisch
authors.forename: Nancy
authors.initials: N
authors.lastname: Steiner
authors.forename: Lorenz
authors.initials: L
authors.lastname: Fülle
authors.forename: Veronika
authors.initials: V
authors.lastname: Lukacs-Kornek
authors.forename: Daniel
authors.initials: D
authors.lastname: Degrandi
authors.forename: Philipp
authors.initials: P
authors.lastname: Dresing
authors.forename: Judith
authors.initials: J
authors.lastname: Alferink
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.forename: Heike
authors.initials: H
authors.lastname: Weighardt
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulas
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D060833:Cellular Microenvironment / Q000276:immunology*; D054414:Chemokine CCL17 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017471:Receptors, Interferon / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D039481:CD11b Antigen; D054414:Chemokine CCL17; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D015847:Interleukin-4; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C499538:Ccl17 protein, mouse
keywords: DCs; GM-CSF; IFN-γ receptor; IL-4; Spleen