Type III IFNs Are Produced by and Stimulate Human Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDC) are rare cells found in peripheral blood and lymphoid tissues. pDC are considered to be professional type I IFN-producing cells and produce 10- to 100-fold more IFN-alpha than other cell types in response to enveloped viruses or synthetic TLR7 and TLR9 agonists. In this study, purified pDC were found to express high levels of IFN-lambda receptor mRNA, as well as cell-surface IFN-lambda receptor. We have developed intracellular flow cytometry assays using Abs to IFN-lambda 1/3 or -lambda 2 to assess the expression of IFN-lambda proteins by pDC. We observed that a subset of human pDC expresses only intracellular IFN-alpha, whereas another subset produces both IFN-alpha and IFN-lambda after stimulation with virus or the TLR9 agonist, CpG A; the cells that coexpressed IFN-alpha and IFN-lambda were the cells with the highest levels of IFN-alpha expression. Ab cross-linking of CD4 or CD303 molecules on pDC inhibited both HSV-induced IFN-lambda and IFN-alpha production. Like the production of IFN-alpha, the HSV-induced IFN-lambda production in pDC was mediated through TLR9 and independent of virus replication. Exogenous IFN-lambda treatment of pDC resulted in increased virus-induced expression of both IFN-alpha and IFN-lambda. In addition, both exogenous IFN-lambda and -alpha inhibited dexamethasone-induced apoptosis of pDC. We conclude that pDC are major producers of IFN-lambda 1 and -lambda 2 in response to viral stimulation and also express functional receptors for this cytokine. Thus, IFN-lambda can serve as an autocrine signal to strengthen the antiviral response of pDC by increasing IFN-alpha and IFN-lambda production, resulting in prolonged pDC survival. The Journal of Immunology, 2012, 189: 2735-2745.