Human dendritic cells stimulated via TLR7 and/or TLR8 induce the sequential production of Il-10, IFN-gamma, and IL-17A by naive CD4+ T cells.
Depending upon which TLRs are triggered, dendritic cells (DCs) may orient the differentiation of naive CD4(+) T cells toward either Th1, Th2, regulatory T cells, or the recently defined Th17 lineage. In this study, we report that a dual stimulation of TLR4 and TLR7/8 with LPS plus R848 leads human monocyte-derived DCs (MoDCs) to produce multiple pro- and anti-inflammatory cytokines, including IL-10, IL-12, and IL-23. Surprisingly, a significant variability in the up-regulation of these cytokines is observed in DCs obtained from various healthy donors, with approximately one of three being "high responders." High responding MoDCs stimulated via TLR4 and TLR7/8 induce naive allogeneic CD4(+) T cell to secrete sequentially IL-10 and IFN-gamma, and eventually IL-17A, whereas low responding MoDCs only stimulate IFN-gamma production. Both TLR7 and TLR8 play a central role in this phenomenon: TLR4 triggering with LPS up-regulates TLR7 expression on human MoDCs from high responders, silencing of either TLR7 or TLR8 mRNAs inhibits cytokine production in LPS plus R848-treated MoDCs, and plasmacytoid DCs constitutively expressing high levels of TLR7 induce the production of IL-10, IFN-gamma, and IL-17A by naive T cells when stimulated with R848 alone. Collectively, our results illustrate the synergy between TLR4 and TLR7/8 in controlling the sequential production of regulatory and proinflammatory cytokines by naive CD4(+) T cells. The observed polymorphism in DC responses to such TLR-mediated stimuli could explain differences in the susceptibility to infectious pathogens or autoimmune diseases within the human population.
Lombardi
Vincent
V
Research and Development, Stallergènes SA, France.
Van Overtvelt
Laurence
L
Horiot
Stéphane
S
Moingeon
Philippe
P
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000502:physiology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000502:physiology*
C508717:IL17A protein, human; D007093:Imidazoles; D018836:Inflammation Mediators; D020381:Interleukin-17; D008070:Lipopolysaccharides; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D016753:Interleukin-10; D007371:Interferon-gamma; C402365:resiquimod