title: Contact-dependent abrogation of bone marrow-derived plasmacytoid dendritic cell differentiation by murine mesenchymal stem cells.
abstract: Plasmacytoid dendritic cells (pDCs) are rare central regulators of antiviral immunity and unsurpassed producers of interferon-α (IFN-α). Despite their crucial role as a link between innate and adaptive immunity, little is known about the modulation of pDC differentiation by other bone marrow (BM) cells. In this study, we investigated the modulation of pDC differentiation in Flt-3 ligand (Flt3L)-supplemented BM cultures, using highly purified mesenchymal stem cells (MSCs) that were FACS-isolated from murine BM based on surface marker expression and used after in vitro expansion. Initial analysis revealed an almost complete inhibition of BM-derived pDC expansion in the presence of >2% MSC. This inhibition was cell contact-dependent and soluble factor-independent, as indicated by trans-well experiments. The abrogation of functional pDC development by MSCs was confirmed after TLR9 stimulation, revealing a complete, contact-dependent suppression of the IFN-a producing capacity of pDCs in Flt3L MSC BM co-cultures. MSC selectively inhibited pDC development in contrast to myeloid DC development, as indicated by the significantly increased numbers of myeloid DC in Flt3L-supplemented BM cultures. The absence of significant MSC-mediated inhibitory effects on myeloid DC differentiation was confirmed by additional experiments in GM-CSF/IL-4-supplemented BM cultures. In summary, we describe a novel contact-dependent immunomodulatory mechanism of MSC that targets the BM-derived expansion of functional pDCs.
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Germany. Electronic address: Holger.Hackstein@immunologie.med.uni-giessen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Germany.
authors.forename: Inna
authors.initials: I
authors.lastname: Tschipakow
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bein
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen und Marburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Nold
authors.affiliation: Department of Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen und Marburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.affiliation: Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Germany.
authors.forename: Nelli
authors.initials: N
authors.lastname: Baal
mesh_terms: D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D016898:Interferon-alpha; D008565:Membrane Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C084881:flt3 ligand protein
keywords: Dendritic cells; Inflammation; Interferon-a; Mesenchymal stromal cell; Toll-like receptor