IFN-alpha promotes definitive maturation of dendritic cells generated by short-term culture of monocytes with GM-CSF and IL-4.
Dendritic cells (DC) generated in vitro have to be viable and phenotypically mature to be capable of inducing T cell-mediated immunity after in vivo administration. To facilitate optimization of DC-based vaccination protocols, we investigated whether the cytokine environment and the mode of activation affect maturation and survival of DC derived from monocytes by a short-term protocol. Monocytes cultured for 24 h with granulocyte macrophage-colony stimulating factor and interleukin-4 were stimulated with proinflammatory mediators for another 36 h to generate mature DC. Additional activation with CD40 ligand and interferon (IFN)-gamma increased viability of DC and promoted definitive maturation as defined by maintenance of a mature phenotype after withdrawal of cytokines. Addition of IFN-alpha to DC cultures prior to stimulation further enhanced definitive maturation: IFN-alpha-primed DC expressed high levels of costimulatory molecules and CC chemokine receptor 7 (CCR7) up to 5 days after cytokine withdrawal. Compared with unprimed DC, IFN-alpha-primed DC displayed equal capacity to migrate upon CCR7 ligation and to prime antigen-specific T helper cell as well as cytolytic T cell responses. In conclusion, we show that optimal maturation and survival of monocyte-derived DC require multiple activation signals. Furthermore, we identified a novel role for IFN-alpha in DC development: IFN-alpha priming of monocytes promotes definitive maturation of DC upon activation.
Dauer
Marc
M
Section of Gastroenterology and Division Clinical Pharmacology, Medizinische Klinik Innenstadt, University of Munich, Munich, Germany.
Schad
Katharina
K
Junkmann
Jana
J
Bauer
Christian
C
Herten
Jan
J
Kiefl
Rosemarie
R
Schnurr
Max
M
Endres
Stefan
S
Eigler
Andreas
A
D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000097:blood; D015847:Interleukin-4 / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology
C515370:CCR7 protein, human; D016898:Interferon-alpha; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor