All cells possess signaling pathways designed to trigger antiviral responses, notably characterized by type I interferon (IFN) production, upon recognition of invading viruses. RNA transferred via noninfectious and/or noncanonical viral/cellular carriers. Therefore, the pDC response likely bypasses innate signaling blockages induced by virus within infected cells. Importantly, the requirement for cell-cell contact is increasingly recognized as a hallmark of the pDC-mediated antiviral state, triggered by evolutionarily divergent RNA viruses. INTRODUCTION The innate immune response represents the first line of defense against many pathogens. This response is initiated by the recognition of pathogen-associated molecular patterns SCH 727965 kinase activity assay (PAMPs) by cellular pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs). This leads to the production of antiviral molecules, including interferons (IFNs), a broad range of interferon-stimulated genes (ISGs), and inflammatory cytokines. This first line of host response suppresses viral spread and jump-starts the adaptive immune response. Dendritic cells (DCs) serve as unique immune sentinels, surveying tissues, sensing infection and inflammation, sampling potential antigens, integrating these peripheral cues, and instructing both the innate and the adaptive immune system accordingly. Through this array of specialized functions, DCs orchestrate powerful pathogen-directed immunity and are pivotal in the regulation of viral pathogenesis. Different DC subsets respond in unique and specialized fashions to orchestrate antiviral responses. Among these, plasmacytoid dendritic cells (pDCs) are key players in the early antiviral responses, notably by their ability to produce a large amount of type I IFN (IFN- and IFN-) (i.e., 1,000-fold more than other cell types) and type III IFN (IFN-/interleukin-28 [IL-28]/IL-29) (reviewed in reference 1). Their response is rapid and triggered mainly by the endosomal sensors TLR7 and TLR9, which recognize viral nucleic acids (RNA and DNA, respectively). The type I IFN response induced by pDCs is thought to be a key part of their role in the resolution of viral infections (1), especially at the acute phase. Direct evidence is still limited in human studies; nevertheless, an association between the resolution of viral infections and pDC functionality has been reported for certain viruses. For example, pDCs from elite controllers, a subset of human immunodeficiency virus type 1 (HIV-1)-infected CD8B patients who sustain undetectable viral loads in the absence of therapy, were found to induce notably greater production of IFN- than SCH 727965 kinase activity assay pDCs from viremic patients (2). Similarly, a study conducted on dengue virus (DENV)-infected patients showed that the number of circulating pDCs and their attendant IFN responses were inversely associated with viral load and disease severity (3). Studies using mouse models also provide evidence for the role of pDCs in the clearance of viral infections (1). For example, the depletion of pDCs revealed that they are central for early IFN- production in SCH 727965 kinase activity assay response to several systemic viral infections, as first reported for mouse hepatitis virus (MHV) (4) and later for, e.g., lymphocytic choriomeningitis virus (LCMV), respiratory syncytial virus (RSV), and herpes simplex virus 1/2 (HSV-1/2) (1, 5,C8). Importantly, pDCs promoted virus control and host survival in some of these models (5, 6, 8). This Gem highlights the current working models for the activation of an antiviral state by pDCs via cell-cell contacts with infected cells. We also discuss how the pDC response contributes to the control of viral infections, likely, at least in part, via their ability to produce large amounts of IFN-. pDC ACTIVATION BY CELL-CELL CONTACT WITH VIRUS-INFECTED CELLS Recent studies revealed that pDCs sense viral infections when in physical contact with infected cells (reviewed in reference 9). This previously unsuspected feature of innate sensing is increasingly recognized as a hallmark of the pDC-mediated antiviral state, triggered by evolutionarily distant RNA viruses (i.e., FUNCTIONS OF pDC, A MASTER IFN-PRODUCING CELL TYPE The regulatory functions of pDCs.