Article first published online: 14 MAR 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 5, pages 1705–1715, May 2013
How to Cite
Yoshio, S., Kanto, T., Kuroda, S., Matsubara, T., Higashitani, K., Kakita, N., Ishida, H., Hiramatsu, N., Nagano, H., Sugiyama, M., Murata, K., Fukuhara, T., Matsuura, Y., Hayashi, N., Mizokami, M. and Takehara, T. (2013), Human blood dendritic cell antigen 3 (BDCA3)+ dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus. Hepatology, 57: 1705–1715. doi: 10.1002/hep.26182
Potential conflict of interest: Nothing to report.
Supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan and a Grant-In-Aid from the Ministry of Health, Labor, and Welfare of Japan.
- Issue published online: 22 APR 2013
- Article first published online: 14 MAR 2013
- Accepted manuscript online: 5 DEC 2012 02:51AM EST
- Manuscript Accepted: 13 NOV 2012
- Manuscript Received: 2 JUL 2012
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)