Plasmacytoid dendritic cells (pDCs) are a unique dendritic cell subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the pathogenesis of autoimmune diseases characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. Here, we review recent progress from the field of pDC biology, focusing on: the molecular mechanisms that regulate pDC development and functions; the pathways involved in their sensing of pathogens and endogenous nucleic acids; the function of pDCs at mucosal sites; and their roles in infections, autoimmunity and cancer.

Summary Plasmacytoid dendritic cells (pDCs) mediate type I interferon (IFN-I) responses to viruses that are recognized through the Toll-like receptor 7 (TLR7) or TLR9 signaling pathway. However, it is unclear how pDCs regulate the antiviral responses via innate and adaptive immune cells. We generated diphtheria toxin receptor transgenic mice to selectively deplete pDCs by administration of diphtheria toxin. pDC-depleted mice were challenged with viruses known to activate pDCs. In murine cytomegalovirus (MCMV) infection, pDC depletion reduced early IFN-I production and augmented viral burden facilitating the expansion of natural killer (NK) cells expressing the MCMV-specific receptor Ly49H. During vesicular stomatitis virus (VSV) infection, pDC depletion enhanced early viral replication and impaired the survival and accumulation of virus-specific cytotoxic T lymphocytes. We conclude that pDCs mediate early antiviral IFN-I responses and influence the accrual of virus-specific NK or CD8+ T cells in a virus-dependent manner.

Summary Plasmacytoid dendritic cells (pDCss) are bone marrow-derived cells that secrete large amounts of type I interferon (IFN) in response to viruses. Type I IFNs are pleiotropic cytokines with antiviral activity that also enhance innate and adaptive immune responses. Viruses trigger activation of pDCss and type I IFN responses mainly through the Toll-like receptor pathway. However, a variety of activating and inhibitory pDCs receptors fine tune the amplitude of type I IFN responses. Chronic activation and secretion of type I IFN in the absence of infection can promote autoimmune diseases. Furthermore, while activated pDCss promote immunity and autoimmunity, resting or alternatively activated pDCss may be tolerogenic. The various roles of pDCss have been extensively studied in vitro and in vivo with depleting antibodies. However, depleting antibodies cross-react with other cell types that are critical for eliciting protective immunity, potentially yielding ambiguous phenotypes. Here we discuss new approaches to assess pDCs functions in vivo and provide preliminary data on their potential roles during viral infections. Such approaches would also prove useful in the more specific evaluation of how pDCss mediate tolerance and autoimmunity. Finally, we discuss the emergent role of pDCss and one of their receptors, tetherin, in human immunodeficiency virus pathogenesis.

Imiquimod is a synthetic compound with antitumor properties; a 5% cream formulation is successfully used to treat skin tumors. The antitumor effect of imiquimod is multifactorial, although its ability to modulate immune responses by triggering TLR7/8 is thought to be key.