title: CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2.
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.
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany. juergenR@miltenyibiotec.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Röck
authors.forename: Erik
authors.initials: E
authors.lastname: Schneider
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Grün
authors.forename: Andreas
authors.initials: A
authors.lastname: Grützkau
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schmitz
authors.forename: Gregor
authors.initials: G
authors.lastname: Winkels
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000595:Amino Acid Sequence; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured / Q000378:metabolism; D018899:CpG Islands; D003713:Dendritic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D037181:Lectins, C-Type / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D051966:Phospholipase C gamma / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C443299:CLEC4C protein, human; D020672:I-kappa B Proteins; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D000072000:NF-KappaB Inhibitor alpha; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma