Sensitization to TLR7 agonist in IFN-beta-preactivated dendritic cells.
TLRs interact with a growing list of pathogen-derived products and these interactions drive the activation of innate and adaptive immune responses. Dendritic cells (DC) play a key role in these events expressing a heterogeneous repertoire of TLRs. We have previously demonstrated the production of type I IFNs in DC following bacterial infections and TLR triggering. In this study, we sought to characterize the transcriptome specifically induced in human DC by IFN-beta production stimulated upon LPS treatment. To this aim, by using cDNA microarrays, we compared the transcriptome of DC following LPS treatment in the absence or presence of neutralizing anti-type I IFN Abs. Interestingly, we found that the expression of TLR7 was induced during LPS-induced maturation of DC in a type I IFN-dependent manner. The induction of TLR7 in maturing DC was mainly a consequence of the transcriptional activity of IRF-1, whose binding site was located within TLR7 promoter. Moreover, we also demonstrated that "priming" of immature DC, that usually express TLR8 but not TLR7, with exogenous IFN-beta induced a functionally active TLR7. In fact, treatment with the TLR7-specific ligand 3M-001 up-regulated the expression of CD83, CD86, and CD38 in IFN-beta-primed DC but not in immature DC. Therefore, a robust enhancement in proinflammatory as well as regulatory cytokines was observed. These data suggest that TLR4-mediated type I IFN release activates specific transcription programs in DC amplifying the expression of pathogen sensors to correctly and combinatorially respond to a bacterial as well as viral infection.
Severa
Martina
M
Department of Infectious, Parasitic, and Immuno-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
Remoli
Maria Elena
ME
Giacomini
Elena
E
Annibali
Viviana
V
Gafa
Valerie
V
Lande
Roberto
R
Tomai
Mark
M
Salvetti
Marco
M
Coccia
Eliana M
EM
D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000502:physiology; D016899:Interferon-beta / Q000502:physiology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000096:biosynthesis / Q000378:metabolism
D000954:Antigens, Surface; D016207:Cytokines; D018836:Inflammation Mediators; D050856:Interferon Regulatory Factor-1; D008024:Ligands; D008070:Lipopolysaccharides; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D016899:Interferon-beta