EMBO young Investigator LectureStimulation of plasmacytoid Dendritic Cells by the Yellow fever vaccine

Although representing a rare cell type of the immune system, plasmacytoid dendritic cells (pDCs) are the most important source of type I interferon (IFN-I) upon viral infection. These high secretion levels of IFN-I in response to viruses not only have direct inhibitory effects on viral replication, but also activate many other immune cells, such as natural killer cells, B cells, T cells and myeloid DCs, therefore strengthening adaptive immune mechanisms. We investigated the mechanism by which the yellow fever vaccine 17D, a widely-used live attenuated vaccine, stimulates human pDCs to produce IFN-I. We showed that productive infection of human pDCs by cell-free 17D triggered a RIG-I-like receptor (RLR)-dependent IFN-I response. The RIG-I downstream kinase TBK1 and the transcription factor IRF3 were phosphorylated, suggesting that the whole RLR signaling cascade was activated in pDCs. By contrast, pDCs sensing of 17D-infected cells induced a TLR7-dependent, replication-independent IFN-I response. We characterized in detail the mechanisms by which 17D-infected cells stimulate pDCs. Cells producing immature 17D particles were more potent at stimulating pDCs than cells releasing mature virions. Additionally, cells replicating a release-deficient 17D mutant or a 17D subgenomic RNA lacking structural protein-coding sequences participated in pDC stimulation. These viral RNAs free of viral core components were transported to pDCs in an exosome-independent manner. Our study reveals that human pDCs are armed to sense replicative viral RNA, and, depending on its delivery route, a virus is able to stimulate the TLR or the RLR signaling pathway in the same target cell. Our work also provides new insights into the mechanisms by which infected cells stimulate pDCs to induce an antiviral response.