A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection

Abstract

Following the discovery of plasmacytoid dendritic cells (pDCs) and of their extraordinary ability to produce type I IFNs (IFN-I) in response to TLR7 and TLR9 stimulation, it is assumed that their main function is to participate in the antiviral response. There is increasing evidence suggesting that pDCs and/or IFN-I can also have a detrimental role in a number of inflammatory and autoimmune diseases, in the context of chronic viral infections and in cancers. Whether these cells should be targeted in patients and how much of their biology is connected to IFN-I production remains unclear and is discussed here.

Figure 1.

The central role of pDCs and the produced IFN-I in promoting inflammatory and autoimmune diseases. IFN-I and IFN-III are produced by pDCs in response to signals delivered by TLR7 and/or TLR9 in response to the sensing of self–nucleic acids. The accumulation of self-DNA and -RNA in the endosomes can be mediated by complexing with antimicrobial peptides, often induced by tissue injury, by anti–double stranded DNA (dsDNA)/anti–small nuclear ribonucleoproteins (snRNP) or via the uptake of DNA released by NETosis. The secreted IFN will promote the induction of many ISGs and will directly impact immune cells to promote the generation of autoantibody-producing plasma cells and autoreactive T cells. Mo, monocyte; NET, neutrophil extracellular traps.

Figure 2.

CD4-mediated endocytosis of HIV-1 leads to persistent/repeated IFN-I induction in pDCs. HIV-1/CD4 traffics predominantly to early and recycling endosomes, where HIV-1 genomic RNA interacts with TLR7 to activate MYD88, NFκB, IRF7, and IFN-I, leading to repeated response to TLR7 stimulation and persistent IFN induction. In contrast, influenza virus is endocytosed further to late endosomes or lysosomes, where the cleaved TLR7* responds to the flu genomic RNA more rapidly and transiently to activate IRF7 and NFκB. The low pH–induced fusion of flu is critical for flu entry and infection. P, phosphorylation; E, endosome.

Figure 3.

Induction of inflammatory or immature pDCs (ipDCs) during chronic HIV-1 infection. HIV-1 activates pDCs via CD4-dependent endocytosis and HIV-1 RNA-mediated TLR7 activation (1). Persistent activation of pDCs by HIV-1 leads to accumulation of ipDCs (2). ipDCs deplete and impair T cells via unclearly defined IFN-dependent mechanisms (3). Targeting the ipDC/IFN-I axis can rescue anti-HIV T cells to help control HIV-1 (4). IPC, IFN-producing cell; ipDC, immature pDC.