Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells.
Two different CpG oligonucleotides (ODN) were used to study the regulation of type I IFN in human plasmacytoid dendritic cells (PDC): ODN 2216, a CpG-A ODN, known to induce high amounts of IFN-alpha in PDC, and ODN 2006, a CpG-B ODN, which is potent at stimulating B cells. CpG-A ODN showed higher and prolonged kinetics of type I IFN production compared with that of CpG-B ODN. In contrast, CpG-B ODN was more active than CpG-A ODN in stimulating IL-8 production and increasing costimulatory and Ag-presenting molecules, suggesting that CpG-A and CpG-B trigger distinct regulatory pathways in PDC. Indeed, CpG-A ODN, but not CpG-B ODN, activated the type I IFNR-mediated autocrine feedback loop. PDC were found to express high constitutive levels of IFN regulatory factor (IRF)7. IRF7 and STAT1, but not IRF3, were equally up-regulated by both CpG-A and CpG-B. CD40 ligand synergistically increased CpG-B-induced IFN-alpha independent of the IFNR but did not affect CpG-B-induced IFN-beta. In conclusion, our studies provide evidence for the existence of two distinct regulatory pathways of type I IFN synthesis in human PDC, one dependent on and one independent of the IFNR-mediated feedback loop. The alternate use of these pathways is based on the type of stimulus rather than the quantity of IFN-alphabeta available to trigger the IFNR. Constitutive expression of IRF7 and the ability to produce considerable amounts of IFN-alpha independent of the IFNR seem to represent characteristic features of PDC.
Kerkmann
Miren
M
Department of Internal Medicine, Division of Clinical Pharmacology, University of Munich, Munich, Germany.
Rothenfusser
Simon
S
Hornung
Veit
V
Towarowski
Andreas
A
Wagner
Moritz
M
Sarris
Anja
A
Giese
Thomas
T
Endres
Stefan
S
Hartmann
Gunther
G
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000954:Antigens, Surface / Q000096:biosynthesis; D023201:CD40 Ligand / Q000494:pharmacology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004338:Drug Combinations; D025461:Feedback, Physiological / Q000276:immunology; D006801:Humans; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I / Q000096:biosynthesis* / Q000378:metabolism; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007700:Kinetics; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D011971:Receptors, Immunologic; D017471:Receptors, Interferon / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; C443299:CLEC4C protein, human; C408982:CPG-oligonucleotide; D016207:Cytokines; D004268:DNA-Binding Proteins; D004338:Drug Combinations; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016898:Interferon-alpha; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta