title: Self-priming determines high type I IFN production by plasmacytoid dendritic cells.
abstract: Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context.
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Sarah
authors: S
authors: Kim
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Vera
authors: V
authors: Kaiser
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Esther
authors: E
authors: Beier
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Matthias
authors: M
authors: Bechheim
authors: Center of Integrated Protein Science (CIPS-M), Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, University of Munich, 80336 Munich, Germany.
authors: Margit
authors: M
authors: Guenthner-Biller
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Andrea
authors: A
authors: Ablasser
authors: Center of Integrated Protein Science (CIPS-M), Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, University of Munich, 80336 Munich, Germany.
authors: Michael
authors: M
authors: Berger
authors: Center of Integrated Protein Science (CIPS-M), Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, University of Munich, 80336 Munich, Germany.
authors: Stefan
authors: S
authors: Endres
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Gunther
authors: G
authors: Hartmann
authors: Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
authors: Veit
authors: V
authors: Hornung
mesh_terms: D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis*; D016898:Interferon-alpha / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D007370:Interferon Type I; D016898:Interferon-alpha; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors
keywords: CpG-A; CpG-B; TLR9; Type I IFN; pDC