title: Interferon-alpha disables dendritic cell precursors: dendritic cells derived from interferon-alpha-treated monocytes are defective in maturation and T-cell stimulation.
abstract: Dendritic cells (DC) can be derived from monocytes in vitro by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). It is unknown whether this regimen reflects DC differentiation from blood precursors under physiological conditions. Induction of DC development from monocytes by interferon-alpha (IFN-alpha) may occur in vivo during infection or inflammation and thus may represent a more physiological approach to DC differentiation in vitro. Here, we show that incubation of GM-CSF-cultured monocytes with IFN-alpha does not induce DC differentiation: cells maintain their original phenotype and cytokine secretion pattern. Even after stimulation with pro-inflammatory or T-cell-derived activation signals, IFN-alpha-treated monocytes do not develop DC characteristics. Addition of IL-4 during stimulation of IFN-alpha-treated monocytes results in the rapid development of DC-like cells expressing co-stimulatory molecules, CD83 and chemokine receptor CCR7, indicating that some degree of developmental plasticity is preserved. However, DC pre-activated with IFN-alpha are less effective in inducing allogeneic or antigen-specific autologous T-cell proliferation, produce less IL-12 and express lower levels of CCR7 compared to DC generated by culture with GM-CSF and IL-4. Incubating GM-CSF-cultured monocytes simultaneously with IFN-alpha and IL-4 does not affect phenotypic maturation of DC, but reduces IL-12 production upon pro-inflammatory activation. We conclude that: (1) IFN-alpha fails to induce DC differentiation and thus cannot replace IL-4 in generating DC from monocytes in vitro; and (2) the presence of IFN-alpha prior to or during differentiation of DC from monocyte precursors alters their response to maturation stimuli and may affect their capacity to stimulate T helper type 1 immune responses in vivo.
authors.affiliation: Section of Gastroenterology, Medizinische Klinik Innenstadt, University of Munich, Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Dauer
authors.forename: Katrin
authors.initials: K
authors.lastname: Pohl
authors.forename: Bianca
authors.initials: B
authors.lastname: Obermaier
authors.forename: Tobias
authors.initials: T
authors.lastname: Meskendahl
authors.forename: Julian
authors.initials: J
authors.lastname: Röbe
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Andreas
authors.initials: A
authors.lastname: Eigler
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D003911:Dextrans / Q000493:pharmacokinetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C515370:CCR7 protein, human; D016207:Cytokines; D003911:Dextrans; D016898:Interferon-alpha; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018664:Interleukin-12; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor