Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance

Abstract

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.

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

“…As pDCs have shown to control certain immune responses through the production of IFN-I, [7][8][9][10][11][12][13][14] we assessed the contribution of the IFN-I signaling to the control of the development of acute DSS-induced colitis using Ifnar1 À / À mice, which lacking IFN-a/b receptor I (IFNAR1). 34 Unexpectively, there was no substantial difference in the BW loss between WT and Ifnar1 À / À mice following oral DSS administration (Supplementary Figure S2a).…”

“…[4][5][6] On the other hand, pDCs are specialized in endosomal TLR7/9-mediated recognition of viral nucleic acids (NAs) and respond with the massive secretion of type I interferon (IFN-I). [7][8][9] Therefore, pDCs have been considered as important mediators of antiviral responses. [7][8][9] Furthermore, recent studies have suggested that the activation of pDCs by recognition of self-NA causes elevated IFN-I levels, 10 and this process contributes to the induction of pathogenesis in psoriasis 11 and systemic lupus erythematosus (SLE).…”

“…[7][8][9] Therefore, pDCs have been considered as important mediators of antiviral responses. [7][8][9] Furthermore, recent studies have suggested that the activation of pDCs by recognition of self-NA causes elevated IFN-I levels, 10 and this process contributes to the induction of pathogenesis in psoriasis 11 and systemic lupus erythematosus (SLE). [12][13][14] The intestine is the largest compartment of the immune system that is lined by a single layer of epithelium harboring commensal bacteria.…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…PDCs are the major cellular source of type I IFN (especially IFN-a) [3], which induces a strong antiviral state [17,18]. The main PDCs pathogen recognition receptors reside in the endosomes and consist of Toll-like receptors (TLR)-7 and -9, whose engagement leads to powerful type I IFN secretion, followed by DCs differentiation [15,19,20]. TLR-7 and TLR-9 respond to viral RNA and DNA that reach endosomes upon cell infection or autophagy [15].…”

“…In addition to type I IFN, PDCs produce other cytokines, including TNF-a IL-6, and CXCL8 [17,22], and inflammatory chemokines such as CXCL9, CXCL10, CCL3, CCL4, and CCL5 [20,23]. Thus, PDCs influence cells of both innate and adaptive immune responses [17].…”