Human Blood Dendritic Cell Antigen 3 (BDCA3)+ Dendritic Cells Are a Potent Producer of Interferon-λ in Response to Hepatitis C Virus

被引：86

作者：

Yoshio, Sachiyo ^{[1
]}

Kanto, Tatsuya ^{[1
]}

Kuroda, Shoko ^{[1
]}

Matsubara, Tokuhiro ^{[1
]}

Higashitani, Koyo ^{[1
]}

Kakita, Naruyasu ^{[1
]}

Ishida, Hisashi ^{[1
]}

Hiramatsu, Naoki ^{[1
]}

Nagano, Hiroaki ^{[2
]}

Sugiyama, Masaya ^{[3
]}

Murata, Kazumoto ^{[3
]}

Fukuhara, Takasuke ^{[4
]}

Matsuura, Yoshiharu ^{[4
]}

Hayashi, Norio ^{[5
]}

Mizokami, Masashi ^{[3
]}

Takehara, Tetsuo ^{[1
]}

机构：

[1] Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Suita, Osaka 5650871, Japan

[2] Osaka Univ, Grad Sch Med, Dept Surg, Suita, Osaka 5650871, Japan

[3] Natl Ctr Global Hlth & Med, Res Ctr Hepatitis & Immunol, Ichikawa, Japan

[4] Osaka Univ, Microbial Dis Res Inst, Dept Mol Virol, Suita, Osaka 5650871, Japan

[5] Kansai Rosai Hosp, Kobe, Hyogo, Japan

来源：

HEPATOLOGY | 2013年 / 57卷 / 05期

关键词：

GENETIC-VARIATION; IMMUNE-RESPONSE; VIRAL-INFECTION; IFN-LAMBDA; IL28B; CULTURE; REPLICATION; RECOGNITION; ACTIVATION; CLEARANCE;

D O I：

10.1002/hep.26182

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

The polymorphisms in the interleukin (IL)-28B (interferon-lambda [IFN]-lambda 3) 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) 1 DCs were discovered as a producer of IFN-lambda 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-beta (TRIF)-specific inhibitor, or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-lambda 1, IL-28A/IFN-lambda 2, 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-lambda s, 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-lambda 3, the ability of which is superior in subjects with IL-28B major genotype. (HEPATOLOGY 2013;57:1705-1715)

引用

页码：1705 / 1715

页数：11