PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible for augmented production of type I interferon.
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.
Watarai
Hiroshi
H
Laboratories for Immune Regulation and Host Defense, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. hwatarai@rcai.riken.jp
Sekine
Etsuko
E
Inoue
Sayo
S
Nakagawa
Ryusuke
R
Kaisho
Tsuneyasu
T
Taniguchi
Masaru
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D019295:Computational Biology; D016207:Cytokines / Q000032:analysis; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007370:Interferon Type I / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D016207:Cytokines; D017931:DNA Primers; D007370:Interferon Type I; D009419:Nerve Tissue Proteins; C528406:PDC-TREM protein, mouse; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; C483479:Sema6d protein, mouse; D039961:Semaphorins; D051193:Toll-Like Receptors; C484963:Tyrobp protein, mouse