Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells.
Dendritic cell maturation critically modulates antiviral immune responses, and facilitates viral clearance. Hepatitis C virus (HCV) is characterized by its high predisposition to persistent infection. Here, we examined the immune response of human monocyte-derived dendritic cells (MoDCs) to the JFH1 strain of HCV, which can efficiently replicate in cell culture. However, neither HCV RNA replication nor antigen production was detected in MoDCs inoculated with JFH1. None of the indicators of HCV interacting with MoDCs we evaluated were affected, including expression of maturation markers (CD80, 83, 86), cytokines (interleukin-6 and interferon-beta), the mixed lymphocyte reaction, and natural killer (NK) cell cytotoxicity. Strikingly, MoDCs matured by phagocytosing extrinsically-infected vesicles containing HCV-derived double-stranded RNA (dsRNA). When MoDCs were cocultured with HCV-infected apoptotic Huh7.5.1 hepatic cells, there was increased CD86 expression and interleukin-6 and interferon-beta production in MoDCs, which were characterized by the potential to activate NK cells and induce CD4+ T cells into the T helper 1 type. Lipid raft-dependent phagocytosis of HCV-infected apoptotic vesicles containing dsRNA was indispensable to MoDC maturation. Colocalization of dsRNA with Toll-like receptor 3 (TLR3) in phagosomes suggested the importance of TLR3 signaling in the MoDC response against HCV.


CONCLUSIONS
The JFH1 strain does not directly stimulate MoDCs to activate T cells and NK cells, but phagocytosing HCV-infected apoptotic cells and their interaction with the TLR3 pathway in MoDCs plays a critical role in MoDC maturation and reciprocal activation of T and NK cells.
Ebihara
Takashi
T
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Shingai
Masashi
M
Matsumoto
Misako
M
Wakita
Takaji
T
Seya
Tsukasa
T
D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D009000:Monocytes / Q000473:pathology; D010587:Phagocytosis; D012330:RNA, Double-Stranded / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014779:Virus Replication
D016207:Cytokines; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3