Effect of multiple activation stimuli on the generation of Th1-polarizing dendritic cells

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• 作者：Christopher Paustian ; Richard Caspell ; Terrence Johnson ; Peter A. Cohen ; Suyu Shu ; Shuwen Xu ; Brian J. Czerniecki ; Gary K. Koski
• 关键词：Dendritic cell ; IL-12 ; T helper cell ; Toll-like receptor ; Innate immunity
• 刊名：Human Immunology
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：72
• 期：1
• 页码：24-31
• 全文大小：2110 K

文摘

It was originally reported that only a small fraction of total matured dendritic cells (DCs) produced interleukin (IL)–12, but it has never been determined whether different combinations of activating signals now shown to maximize secreted IL-12 do so through increasing output by the same IL-12 producers, or by recruiting additional cytokine-secreting cells. We therefore tested all combinations of bacterial lipopolysaccharide (LPS) (TLR4 ligand), R848 (TLR8 ligand), interferon (IFN)–γ, and CD40L for activating human monocyte-derived dendritic cells (DC), and determined by intracellular flow cytometry that enhanced IL-12 secretion was accomplished in large part by markedly increasing the proportion of cells producing IL-12, with the triple and quadruple combinations recruiting the most DC. This optimization requirement for multiple signals was not reflected in differential Toll-like receptor (TLR) expression by the cells. Interestingly, DCs activated with single TLR ligands plus IFN-γ were capable of responding with a second burst of IL-12 upon later CD40L stimulation, whereas DCs activated with R848 plus LPS were not, despite the trend of the latter for superior polarization of naive T cells toward IFN-γ–secreting Th1. These results have implications for the biology of IL-12–secreting DCs and choice of activation regimen for prospective use in DC-based immunotherapy.