Abstract
Type I interferons (IFNs) derived from plasmacytoid dendritic cells (PDCs) are critical for antiviral responses; however, the mechanisms underlying their production remain unclear. We have identified a receptor, PDC-TREM, which is associated with Plexin-A1 (PlxnA1) on the PDC cell surface and is preferentially expressed after TLR-stimulation. Limited TLR signals induced PDC-TREM expression but failed to induce IFN-alpha production. However, when coupled with Sema6D, a ligand for Plexin-A1, limited TLR-stimulation resulted in PDC-TREM-mediated DAP12-dependent phosphorylation of phosphoinositide 3-kinase (PI3K) and extracellular regulated kinase (Erk) 1/2 at 6-9 h, and IFN-alpha was produced. Inhibition of PDC-TREM expression by pdctrem-shRNA, blocking of PDC-TREM-binding with PlxnA1 by PDC-TREM mAb, and DAP12 deficiency all resulted in greatly reduced PDC-TREM-dependent activation of signaling molecules and IFN-alpha production. Thus, PDC-TREM is responsible for IFN-alpha production, whereas TLR signals are essential for PDC-TREM expression.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal
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Base Sequence
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Blotting, Western
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Cells, Cultured
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Computational Biology
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Cytokines / analysis
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DNA Primers / genetics
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Gene Expression Regulation / immunology*
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Interferon Type I / biosynthesis*
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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Nerve Tissue Proteins / metabolism
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Phosphorylation
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RNA Interference
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Semaphorins / metabolism
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Sequence Analysis, DNA
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Spleen / metabolism
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Toll-Like Receptors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Cytokines
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DNA Primers
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Interferon Type I
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Nerve Tissue Proteins
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PDC-TREM protein, mouse
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Plxna1 protein, mouse
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Receptors, Cell Surface
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Sema6d protein, mouse
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Semaphorins
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Toll-Like Receptors
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Tyrobp protein, mouse