TLR7/8 agonists impair monocyte-derived dendritic cell differentiation and maturation.
Pathogen recognition by TLR activates the innate immune response and is typically followed by the development of an adaptive immune response initiated by antigen presentation. Dendritic cells (DC) are the most efficient APC and express diverse TLRs, including TLR7 and -8, which have been recently identified as targets for ssRNA recognition during viral infection. We have studied the effect of TLR7/8 agonists on DC differentiation and maturation from human monocytes. The synthetic agonist Resiquimod (R-848) or the physiological agonist ssRNA impaired monocyte differentiation to DC phenotypically and functionally. Induced expression of the nonclassical MHC molecules of the CD1 family in DC was inhibited at the protein and mRNA levels, and antigen acquisition was inhibited. Proinflammatory cytokine (including IL-6, IL-8, TNF-alpha, IL-1beta) and IL-10 production were induced during DC differentiation. Cross-talk between TLR4 and TLR7/8 was revealed as immature DC, which had been differentiated in the presence of R-848 were insensitive to LPS-mediated maturation and cytokine production but still induced allostimulation. These data lead us to suggest that ongoing viral activation of TLR7/8 could alter the adaptive immune response by modifying DC differentiation and by down-regulating DC responsiveness to a subsequent bacterial TLR4-mediated signal.
Assier
Eric
E
INSERM U662, Université Paris 7, Institut Universitaire d'Hématologie, Centre Hayem, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75010 Paris, France.
Marin-Esteban
Viviana
V
Haziot
Alain
A
Maggi
Enrico
E
Charron
Dominique
D
Mooney
Nuala
N
D017951:Antigen Presentation; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D009000:Monocytes / Q000502:physiology* / Q000821:virology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*
D016207:Cytokines; D007093:Imidazoles; D008024:Ligands; C495345:TLR4 protein, human; C495348:TLR7 protein, human; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C402365:resiquimod