Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells

J Immunol. 2003 May 1;170(9):4465-74. doi: 10.4049/jimmunol.170.9.4465.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / antagonists & inhibitors
  • Adjuvants, Immunologic / pharmacology
  • Adolescent
  • Adult
  • Aged
  • Antibodies, Monoclonal / metabolism
  • Antigens, Surface / biosynthesis
  • CD40 Ligand / pharmacology
  • Cells, Cultured
  • CpG Islands / immunology*
  • Cytokines / biosynthesis
  • DNA-Binding Proteins / biosynthesis
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Drug Combinations
  • Feedback, Physiological / immunology
  • Humans
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I / biosynthesis*
  • Interferon Type I / metabolism
  • Interferon-alpha / antagonists & inhibitors
  • Interferon-alpha / biosynthesis
  • Interferon-alpha / metabolism
  • Interferon-beta / antagonists & inhibitors
  • Interferon-beta / biosynthesis
  • Kinetics
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins
  • Middle Aged
  • Oligodeoxyribonucleotides / antagonists & inhibitors
  • Oligodeoxyribonucleotides / pharmacology*
  • Plasma Cells / immunology*
  • Plasma Cells / metabolism*
  • Receptor, Interferon alpha-beta
  • Receptors, Immunologic
  • Receptors, Interferon / physiology
  • STAT1 Transcription Factor
  • Signal Transduction / immunology*
  • Trans-Activators / biosynthesis
  • Transcription Factors / biosynthesis
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Adjuvants, Immunologic
  • Antibodies, Monoclonal
  • Antigens, Surface
  • CLEC4C protein, human
  • CPG-oligonucleotide
  • Cytokines
  • DNA-Binding Proteins
  • Drug Combinations
  • IRF3 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Interferon-alpha
  • Lectins, C-Type
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins
  • Oligodeoxyribonucleotides
  • Receptors, Immunologic
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand
  • Receptor, Interferon alpha-beta
  • Interferon-beta