CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2

Eur J Immunol. 2007 Dec;37(12):3564-75. doi: 10.1002/eji.200737711.

Abstract

Plasmacytoid dendritic cells (PDC) are the main type I interferon (IFN-I) producers and play a central role in innate and adaptive immunity. CD303 (BDCA-2) is a type II c-type lectin specifically expressed by human PDC. CD303 signaling induces tyrosine phosphorylation and Src kinase dependent calcium influx. Cross-linking CD303 results in the inhibition of IFN-I production in stimulated PDC. Here, we demonstrate that PDC express a signalosome similar to the BCR signalosome, consisting of Lyn, Syk, Btk, Slp65 (Blnk) and PLCgamma2. CD303 associates with the signaling adapter FcR gamma-chain. Triggering CD303 leads to tyrosine phosphorylation of Syk, Slp65, PLCgamma2 and cytoskeletal proteins. Analogous to BCR signaling, CD303 signaling is likely linked with its internalization by clathrin-mediated endocytosis. Furthermore, CD303 signaling leads to reduced levels of transcripts for IFN-I genes and IFN-I-responsive genes, indicating that the inhibition of IFN-I production by stimulated PDC is at least partially regulated at the transcriptional level. These results support a possible therapeutic value of an anti-CD303 mAb strategy, since the production of IFN-I by PDC is considered to be a major pathophysiological factor in systemic lupus erythematosus patients.

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Agammaglobulinaemia Tyrosine Kinase
  • Amino Acid Sequence
  • Calcium Signaling / physiology
  • Cells, Cultured / metabolism
  • CpG Islands
  • Dendritic Cells / metabolism*
  • Gene Expression Regulation / physiology
  • Humans
  • I-kappa B Proteins / metabolism
  • Interferon Type I / biosynthesis*
  • Interferon Type I / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lectins, C-Type / physiology*
  • Membrane Glycoproteins / physiology*
  • Molecular Sequence Data
  • Multienzyme Complexes / physiology*
  • NF-KappaB Inhibitor alpha
  • Phospholipase C gamma / physiology*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / physiology*
  • Receptors, IgG / physiology
  • Receptors, Immunologic / physiology*
  • Signal Transduction / physiology*
  • Syk Kinase
  • src-Family Kinases / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • CLEC4C protein, human
  • I-kappa B Proteins
  • Interferon Type I
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Multienzyme Complexes
  • NFKBIA protein, human
  • Receptors, IgG
  • Receptors, Immunologic
  • NF-KappaB Inhibitor alpha
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • SYK protein, human
  • Syk Kinase
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Phospholipase C gamma