TLR ligands upregulate RIG-I expression in human plasmacytoid dendritic cells in a type I IFN-independent manner.
Plasmacytoid dendritic cells (pDCs) are professional type I interferon (IFN)-producing cells that play an essential role in antiviral immunity. In many cell types, detection of intracellular pathogens is mostly dependent on endosomal Toll-like receptors (TLRs) and cytosolic sensors, such as retinoic acid-inducible gene I (RIG-I). However, the possible interplay between these two systems has not yet been elucidated. Here we aimed to study the collaboration of endosomal TLRs and RIG-I in primary human pDCs. We found that under steady-state conditions, pDCs express RIG-I at very low level, but the expression of this receptor is rapidly and dramatically upregulated upon stimulation by the TLR7 ligand imiquimod or the TLR9 ligand type A CpG. We also demonstrated that pDCs are able to sense and respond to 5'-triphosphate double-stranded RNA (5'-ppp-dsRNA) only following activation by endosomal TLRs. Experiments on primary pDCs with functionally blocked IFN-α/β receptor 1 (IFNAR1) and those on human pDC leukemia (pDC-L) cells defective in type I IFN secretion indicated that the upregulation of RIG-I expression in pDCs upon stimulation by endosomal TLR occurs in a type I IFN-independent manner. Selective phosphorylation of signal transducer and activator of transcription 1 (STAT1) on tyrosine 701 could be identified as an early signaling event in this process. Our results show that in contrast to many other cell types, where RIG-I expression is induced by type I IFN, in pDCs a disparate mechanism is responsible for the upregulation of RIG-I. Our findings also indicate that along with autophagy, an additional mechanism is operating in pDCs to promote the detection of replicating viruses.
Department of Immunology, Medical and Health Sciences Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Attila
A
Szabo
Department of Immunology, Medical and Health Sciences Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Zoltan
Z
Magyarics
Department of Immunology, Medical and Health Sciences Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Kitti
K
Pazmandi
Department of Haematology and Stem Cell Transplantation, Szent Istvan and Szent Laszlo Hospital of Budapest, Budapest, Hungary.
Laszlo
L
Gopcsa
Department of Immunology, Medical and Health Sciences Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Eva
E
Rajnavolgyi
Department of Immunology, Medical and Health Sciences Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Attila
A
Bacsi
D000634:Aminoquinolines / Q000494:pharmacology; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000077271:Imiquimod; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D010766:Phosphorylation; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D015854:Up-Regulation
D000634:Aminoquinolines; D007370:Interferon Type I; D008024:Ligands; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; D051193:Toll-Like Receptors; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000077271:Imiquimod