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 Blood, 27 August 2009, Vol. 114, No. 9, pp. 1794-1802.
Prepublished online as a Blood First Edition Paper on June 24, 2009; DOI 10.1182/blood-2009-04-216770.

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IMMUNOBIOLOGY

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

Jérémy Di Domizio13, Ariane Blum13, Maighread Gallagher-Gambarelli1,4,5, Jean-Paul Molens13, Laurence Chaperot13, and Joël Plumas13

1 Université Joseph Fourier, Grenoble; 2 Inserm U823, Immunobiologie et immunothérapie des cancers, La Tronche; 3 Etablissement Français du sang (EFS) Rhône-Alpes, Laboratoire R&D, La Tronche; 4 Commissariat à l'Énergie Atomic, Direction des sciences du vivant, institut de recherches en technologies et sciences pour le vivant, Laboratoire d'Etude de la Dynamique des Protéomes, Grenoble; and 5 Inserm U880, Grenoble, France

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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