Human blood dendritic cell antigen 3 (BDCA3)+ dendritic cells are a potent producer of interferon‐λ in response to hepatitis C virus

• Published in: Hepatology (Baltimore, Md.) Vol. 57; no. 5; pp. 1705 - 1715
• Main Authors: Yoshio, Sachiyo, Kanto, Tatsuya, Kuroda, Shoko, Matsubara, Tokuhiro, Higashitani, Koyo, Kakita, Naruyasu, Ishida, Hisashi, Hiramatsu, Naoki, Nagano, Hiroaki, Sugiyama, Masaya, Murata, Kazumoto, Fukuhara, Takasuke, Matsuura, Yoshiharu, Hayashi, Norio, Mizokami, Masashi, Takehara, Tetsuo
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2013
• Subjects: Adult; Antigens, Surface - metabolism; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cells, Cultured; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Dendritic Cells - pathology; Female; Genotype; Hepacivirus - physiology; Humans; Immunity, Innate - physiology; Interferon-gamma - metabolism; Interferons; Interleukins - metabolism; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Liver - metabolism; Liver - pathology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Phenotype; Poly I-C - pharmacology; Thrombomodulin
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.26182

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). Conclusion: 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. (HEPATOLOGY 2013)