Submitted April 15, 2009
Accepted June 15, 2009
TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN
Jeremy Di Domizio, Ariane Blum, Maighread Gallagher-Gambarelli, Jean-Paul Molens, Laurence Chaperot*, and Joel Plumas
Universite Joseph Fourier, Grenoble, France
Inserm, U823, Immunobiologie et immunotherapie des cancers, La Tronche, France
CEA, DSV, iRTSV, Laboratoire d'Etude de la Dynamique des Proteomes, INSERM, U880, Grenoble, France
EFS Rhone-Alpes, Laboratoire R&D, La Tronche, France
* Corresponding author; email: laurence.chaperot{at}efs.sante.fr.
Upon recognition of influenza virus (Flu) via 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 pro-inflammatory cytokines; however, they only induce low-level production of IFN-
. In order to dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of two 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 (IRF) 7 translocation into the nucleus induced by the two TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes MxA, CXCL10 and TRAIL within 4 h 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, demonstrating 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.
