The myeloid pathway to pDCs includes a potential common dendritic cell (DC) progenitor (CDP) ( Naik et al., 2007, Onai et al., 2007) and pDC-biased DC progenitors ( Onai et al., 2013, Schlitzer et al., 2011). Conversely, Flt3L in the absence of other signals is sufficient to drive the development of pDCs and cDCs from myeloid and lymphoid progenitors ( Sathe et al., 2013), consistent with the potential of both progenitor types to produce pDCs in vivo ( Shigematsu et al., 2004). Similar to cDCs, pDC express cytokine receptor Flt3 (CD135) and are strictly dependent on its ligand Flt3L for their development. PDCs are continuously produced in the bone marrow (BM) and emerge as mature cells into the periphery, where they remain non-proliferative and have a relatively short lifespan of several days ( Zhan et al., 2016). This review will primarily focus on IFN-I production as the most prominent, unique, and well-established feature of pDCs, even though other aspects of pDC function such as antigen presentation are undoubtedly important ( Villadangos and Young, 2008). This and other key genetic and functional features of pDCs are shared between humans and mice ( Crozat et al., 2010, Guilliams et al., 2016), highlighting evolutionary conservation of this immune cell type. The speed, magnitude, and broad spectrum of interferon production by pDCs are reflected in the original definition of these cells as “natural interferon-producing cells” ( Colonna et al., 2004, Liu, 2005). pDCs also produce type III interferon (IFN-λ or IL-28/IL-29) and additional cytokines (e.g., TNF-α) and chemokines ( Gilliet et al., 2008, Reizis et al., 2011, Swiecki and Colonna, 2015). pDCs respond to these nucleic acids with massive secretion of IFN-I, which commences within 1–3 h and involves IFN-β and most IFN-α subtypes. pDCs express high levels of endosomal nucleic acid-sensing Toll-like receptors (TLRs) TLR7 and TLR9, which recognize single-stranded RNA and unmethylated CpG motif-containing DNA, respectively. They have the round morphology of a secretory lymphocyte and express low levels of MHC class II that can be upregulated upon activation. PDCs primarily reside in and recirculate through lymphoid organs, where they typically comprise 0.1%–0.5% of nucleated cells.
I sincerely apologize to the researchers whose important original contributions could not be cited due to the limited time frame and scope of this review.ĭevelopment and Transcriptional Regulation of pDCs
Rather than an extensive listing of all pDC-related topics, it focuses on several key areas and concepts and also emphasizes the studies of the last several years that have not been covered in the previous reviews. Solving these questions would hasten the translation of accumulated knowledge into clinical applications focused on pDCs.Īccordingly, the goal of this review is both to summarize the current understanding and to highlight the gaps in our knowledge of pDC biology.
At the same time, this progress brought us to fundamental unanswered questions about the role and mechanism of pDC function. The last 20 years produced extraordinary insights into all aspects of pDC biology, including their development, mechanism of activity, and role in the immune system.
This description was based on extensive prior research by multiple groups (reviewed in Colonna et al., 2004, Liu, 2005) that collectively defined the essential properties of pDCs: secretory “plasmacytoid” morphology akin to that of plasma cells, rapid and massive production of type I interferons (IFN-I) in response to viruses, and the ability to differentiate into conventional dendritic cells (cDCs) in vitro. 2019 marks the 20th anniversary of the definitive description of plasmacytoid dendritic cells (pDCs) as a unique cell type by the Liu and Colonna groups ( Cella et al., 1999, Siegal et al., 1999).