Abstract
Hepatitis C virus (HCV) infects hepatocytes but not dendritic cells (DCs), but DCs effectively mature in response to HCV-infected hepatocytes. Using gene-disrupted mice and hydrodynamic injection strategy, we found the MAVS pathway to be crucial for induction of type III interferons (IFNs) in response to HCV in mouse. Human hepatocytes barely express TLR3 under non-infectious states, but frequently express it in HCV infection. Type I and III IFNs are induced upon stimulation with polyI:C, an analog of double-stranded (ds)RNA. Activation of TLR3 and the TICAM-1 pathway, followed by DC-mediated activation of cellular immunity, is augmented during exposure to viral RNA. Although type III IFNs are released from replication-competent human hepatocytes, DC-mediated CTL proliferation and NK cell activation hardly occur in response to the released type III IFNs. Yet, type I IFNs and HCV-infected hepatocytes can induce maturation of DCs in either human or mouse origin. In addition, mouse CD8+ DCs mature in response to HCV-infected hepatocytes unless the TLR3/TICAM-1 pathway is blocked. We found the exosomes containing HCV RNA in the supernatant of the HCV-infected hepatocytes act as a source of TLR3-mediated DC maturation. Here we summarize our view on the mechanism by which DCs mature to induce NK and CTL in a status of HCV infection.
Highlights
Dendritic cell (DC) maturation is a typical phenotype in virus-infected hosts [1]
Non-infected hepatocytes express only subtle RIG-I/MDA5 and virtually no Toll-like receptor 3 (TLR3), while these sensors are up-regulated in hepatocytes in response to Hepatitis C virus (HCV) RNA [6,7]
We found type III IFN was rapidly produced in CD8+ DCs in a MAVS-dependent manner
Summary
Dendritic cell (DC) maturation is a typical phenotype in virus-infected hosts [1]. Virus antigens (Ags) are efficiently presented on the MHC class I in antigen-presenting DCs. DCs possess RNA sensors in the cytoplasm and endosome, which recognize different structural motifs of RNAs [2]. RIG-I and MDA5 sense 5′-phosphated- or long-(>1 kb) dsRNA motif, respectively, in cytoplasm, while TLR3 and TLR7 sense stem-structured or single-stranded RNA in endosome, respectively [2,3,4]. DC’s Ag-presenting ability is somehow facilitated in response to viral RNA products, and notably, Ag-presenting DCs (CD141+ DCs in human) express TLR3 and RIG-I/MDA5 [5]. Non-infected hepatocytes express only subtle RIG-I/MDA5 and virtually no TLR3, while these sensors are up-regulated in hepatocytes in response to HCV RNA [6,7]. In HCV infection, which of the two pathways, RIG-I/MDA5 or TLR3, is mainly responsible for initial production of IFNs and involved in IFN-lambda induction remained undetermined [6]. We summarize our view on how DC maturation is induced by HCV RNA, which constitutes a part of host anti-HCV immune response
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