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

• Published in: The Journal of immunology (1950) 2009-03, Vol.182 (6), p.3372-3379
• Main Authors: Lombardi, Vincent, Van Overtvelt, Laurence, Horiot, Stéphane, Moingeon, Philippe
• Format: Article
• Language: English
• Subjects: CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - secretion; Cell Differentiation - immunology; Cell Polarity - immunology; Coculture Techniques; Dendritic Cells - immunology; Dendritic Cells - metabolism; Humans; Imidazoles - pharmacology; Inflammation Mediators - metabolism; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-17 - biosynthesis; Lipopolysaccharides - physiology; Monocytes - drug effects; Monocytes - immunology; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 7 - physiology; Toll-Like Receptor 8 - agonists; Toll-Like Receptor 8 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0801969

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.