title: Ly49Q positively regulates type I IFN production by plasmacytoid dendritic cells in an immunoreceptor tyrosine-based inhibitory motif-dependent manner.
abstract: Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during the initial immune response to viral infection. Ly49Q, a C-type lectin-like receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain background, this receptor is required for maximum IFN-α production by pDC. Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4(+) T cell proliferation, and nuclear translocation of the master IFN-α regulator IFN regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of Ly49Q did not affect plasmacytoid dendritic cell-triggering receptor expressed on myeloid cells expression or pDC viability. Genetic complementation revealed that IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2, and SHIP phosphatase activity is dispensable for this function. Finally, we observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling events, leading to IFN regulatory factor 7 nuclear translocation and expression of IFN-I genes in an ITIM-dependent manner that can proceed without the involvement of SHP-1, SHP-2, and SHIP.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Mir Munir A
authors.initials: MM
authors.lastname: Rahim
authors.forename: Lee-Hwa
authors.initials: LH
authors.lastname: Tai
authors.forename: Angela D
authors.initials: AD
authors.lastname: Troke
authors.forename: Ahmad Bakur
authors.initials: AB
authors.lastname: Mahmoud
authors.forename: Elias
authors.initials: E
authors.lastname: Abou-Samra
authors.forename: Justin G
authors.initials: JG
authors.lastname: Roy
authors.forename: Amelia
authors.initials: A
authors.lastname: Mottashed
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ault
authors.forename: Chloe
authors.initials: C
authors.lastname: Corbeil
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Goulet
authors.forename: Haggag S
authors.initials: HS
authors.lastname: Zein
authors.forename: Melisa
authors.initials: M
authors.lastname: Hamilton-Valensky
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyama-Sorimachi
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Makrigiannis
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005816:Genetic Complementation Test / Q000379:methods; D016898:Interferon-alpha / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000276:immunology
chemical_list: C408982:CPG-oligonucleotide; D016898:Interferon-alpha; C527089:Klra17 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D009838:Oligodeoxyribonucleotides