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TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN.

Abstract : On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only low-level production of IFN-alpha. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, was independent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7 triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response.
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https://www.hal.inserm.fr/inserm-00419344
Contributor : Laurence Chaperot <>
Submitted on : Monday, January 25, 2010 - 5:04:36 PM
Last modification on : Friday, March 6, 2020 - 1:44:45 AM
Long-term archiving on: : Wednesday, June 16, 2010 - 12:02:45 AM

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Jérémy Di Domizio, Ariane Blum, Maighread Gallagher-Gambarelli, Jean-Paul Molens, Laurence Chaperot, et al.. TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN.. Blood, American Society of Hematology, 2009, 114 (9), pp.1794-802. ⟨10.1182/blood-2009-04-216770⟩. ⟨inserm-00419344⟩

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