title: Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus.
abstract: The polymorphisms in the interleukin (IL)-28B (interferon-lambda [IFN]-λ3) gene are strongly associated with the efficacy of hepatitis C virus (HCV) clearance. Dendritic cells (DCs) sense HCV and produce IFNs, thereby playing some cooperative roles with HCV-infected hepatocytes in the induction of interferon-stimulated genes (ISGs). Blood dendritic cell antigen 3 (BDCA3)(+) DCs were discovered as a producer of IFN-λ upon Toll-like receptor 3 (TLR3) stimulation. We thus aimed to clarify the roles of BDCA3(+) DCs in anti-HCV innate immunity. Seventy healthy subjects and 20 patients with liver tumors were enrolled. BDCA3(+) DCs, in comparison with plasmacytoid DCs and myeloid DCs, were stimulated with TLR agonists, cell-cultured HCV (HCVcc), or Huh7.5.1 cells transfected with HCV/JFH-1. BDCA3(+) DCs were treated with anti-CD81 antibody, inhibitors of endosome acidification, TIR-domain-containing adapter-inducing interferon-β (TRIF)-specific inhibitor, or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-λ1, IL-28A/IFN-λ2, and IL-28B were quantified by subtype-specific enzyme-linked immunosorbent assay (ELISA). The frequency of BDCA3(+) DCs in peripheral blood mononuclear cell (PBMC) was extremely low but higher in the liver. BDCA3(+) DCs recovered from PBMC or the liver released large amounts of IFN-λs, when stimulated with HCVcc or HCV-transfected Huh7.5.1. BDCA3(+) DCs were able to induce ISGs in the coexisting JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3(+) DCs with anti-CD81 antibody, cloroquine, or bafilomycin A1 reduced HCVcc-induced IL-28B release, whereas BDCA3(+) DCs comparably produced IL-28B upon replication-defective HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3(+) DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3(+) DCs in healthy subjects with IL-28B major (rs8099917, TT) released more IL-28B than those with IL-28B minor genotype (TG).
  
  
  CONCLUSIONS
  Human BDCA3(+) DCs, having a tendency to accumulate in the liver, recognize HCV in a CD81-, endosome-, and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-λ3, the ability of which is superior in subjects with IL-28B major genotype.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Yoshio
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Shoko
authors.initials: S
authors.lastname: Kuroda
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Matsubara
authors.forename: Koyo
authors.initials: K
authors.lastname: Higashitani
authors.forename: Naruyasu
authors.initials: N
authors.lastname: Kakita
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.forename: Masaya
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Murata
authors.forename: Takasuke
authors.initials: T
authors.lastname: Fukuhara
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000328:Adult; D000954:Antigens, Surface / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism*; D007372:Interferons; D007378:Interleukins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D018180:Thrombomodulin; D000095022:Interferon Lambda
chemical_list: D000954:Antigens, Surface; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; D011070:Poly I-C; D018180:Thrombomodulin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C546931:THBD protein, human