IFN-α Skews Monocyte Differentiation into Toll-Like Receptor 7-Expressing Dendritic Cells with Potent Functional Activities

Abstract

IFN-α is an important cytokine for the generation of a protective T cell-mediated immune response to viruses. In this study, we asked whether IFN-α can regulate the functional properties of dendritic cells (DCs). We show that monocytes cultured in the presence of GM-CSF and IFN-α can differentiate into DCs (IFN-α-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-α, IL-1β, and IL-18, and promoted a Th1 response that was independent of IL-12p70 and IL-18, but substantially inhibited by IFN-α neutralization. Furthermore, immature IFN-DCs induced a potent autologous Ag-specific immune response, as evaluated by IFN-γ 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-α following viral stimulation or TLR7-specific stimulation. Taken together, these results illustrate the critical role of IFN-α at the early steps of immune response to pathogens or in autoimmune diseases.

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

“…It will be interesting to study whether the TLR7 sensitivity of other immune cell subsets such as myeloid cells also depends on PDC-derived type I IFN. Of note, type I IFNs were shown to induce TLR7 in macrophages (45), and only myeloid dendritic cells generated in the presence but not in the absence of IFN-␣ were reported to express TLR7 (46).…”

IL-4 Suppresses Dendritic Cell Response to Type I Interferons

“…Although IL-4 is commonly used to generate murine bone marrow (BM)-derived DCs, its effects on DC differentiation and activation are only partially known; mouse BM-DCs generated in the presence of IL-4 appear to be more activated and stronger stimulators of T cells in response to several danger signals (15). Human monocytes grown in the presence of either IL-4 or type I IFNs differentiated into DCs similarly, and IFN-␣ DCs showed a more activated phenotype and function (16,17). Those studies did not, however, examine the effect of IL-4 on the ability of DCs to respond to type I IFNs, a situation resembling a viral infection occurring during Th2-induced parasitosis in vivo.…”

“…Both IFN-␣ and IFN-␤ induce IL-6 production in DCs (17,28). Therefore, we measured by ELISA the levels of IL-6 in the supernatants of BM-DC cultures grown in the presence or absence of IL-4.…”

Prostaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T cell response

“…For instance, many inflammatory mediators such as IFN-a [20][21][22] have been shown to differentiate DC progenitors into Th1-inducing cells (herein named DC1), whereas IL-3 or PGE 2 favor DC2 [23,24]. In addition, vitamin D 3 and TGF-b induce the differentiation of DC able to induce the development of IL-10-producing regulatory T cells [25,26].…”