IFN-alpha skews monocyte differentiation into Toll-like receptor 7-expressing dendritic cells with potent functional activities

• Published in: The Journal of immunology (1950) 2003-10, Vol.171 (7), p.3385-3393
• Main Authors: Mohty, Mohamad, Vialle-Castellano, Alexandra, Nunes, Jacques A, Isnardon, Daniel, Olive, Daniel, Gaugler, Béatrice
• Format: Article
• Language: English
• Subjects: Adult; Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cells, Cultured; Coculture Techniques; Cytokines - biosynthesis; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Epitopes, T-Lymphocyte - biosynthesis; Humans; Interferon-alpha - metabolism; Interferon-alpha - physiology; Interferon-gamma - biosynthesis; Interleukin-12 - physiology; Interleukin-18 - physiology; L Cells (Cell Line); Lymphocyte Activation; Membrane Glycoproteins - biosynthesis; Mice; Monocytes - cytology; Monocytes - immunology; Monocytes - metabolism; Protein Subunits - physiology; Receptors, Cell Surface - biosynthesis; Simplexvirus - immunology; Toll-Like Receptor 7; Toll-Like Receptors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.7.3385

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.