IFN-alpha skews monocyte differentiation into Toll-like receptor 7-expressing dendritic cells with potent functional activities.
IFN-alpha is an important cytokine for the generation of a protective T cell-mediated immune response to viruses. In this study, we asked whether IFN-alpha can regulate the functional properties of dendritic cells (DCs). We show that monocytes cultured in the presence of GM-CSF and IFN-alpha can differentiate into DCs (IFN-alpha-derived DCs (IFN-DCs)). When compared with DCs generated in the presence of GM-CSF and IL-4 (IL-4-derived DCs), IFN-DCs exhibited a typical DC morphology and expressed, in addition to DC markers CD1a and blood DC Ag 4, a similar level of costimulatory and class II MHC molecules, but a significantly higher level of MHC class I molecules. After maturation with CD40 ligand, IFN-DCs up-regulated costimulatory, class I and II MHC molecules and expressed mature DC markers such as CD83 and DC-lysosome-associated membrane protein. IFN-DCs were endowed with potent functional activities. IFN-DCs secreted large amounts of the inflammatory cytokines IL-6, IL-10, TNF-alpha, IL-1beta, and IL-18, and promoted a Th1 response that was independent of IL-12p70 and IL-18, but substantially inhibited by IFN-alpha neutralization. Furthermore, immature IFN-DCs induced a potent autologous Ag-specific immune response, as evaluated by IFN-gamma secretion and expansion of CD8(+) T cells specific for CMV. Also, IFN-DCs expressed a large number of Toll-like receptors (TLRs), including acquisition of TLR7, which is classically found on the natural type I IFN-producing plasmacytoid DCs. Like plasmacytoid DCs, IFN-DCs could secrete IFN-alpha following viral stimulation or TLR7-specific stimulation. Taken together, these results illustrate the critical role of IFN-alpha at the early steps of immune response to pathogens or in autoimmune diseases.
D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D007739:L Cells; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D021122:Protein Subunits / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D018139:Simplexvirus / Q000276:immunology; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016898:Interferon-alpha; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D011956:Receptors, Cell Surface; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma