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Human Dendritic Cells Stimulated via TLR7 and/or TLR8 Induce the Sequential Production of Il-10, IFN-, and IL-17A by Naive CD4⁺ T Cells

Research and Development, Stallergènes SA, France

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-, and eventually IL-17A, whereas low responding MoDCs only stimulate IFN- 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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Phillipe Moingeon, Research and Development, Stallergenes S.A., 6 Rue Alexis de Tocqueville, Antony Cedex 92183, France. E-mail address: pmoingeon{at}stallergenes.fr

² Abbreviations used in this paper: DC, dendritic cell; CBA, cytometric bead array; MoDC, monocyte-derived dendritic cell; pDC, plasmacytoid dendritic cell; Treg, regulatory T cell.