Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus
Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus
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人血树突状细胞抗原 3 (BDCA3)(+) 树突状细胞是对抗丙型肝炎病毒的干扰素 λ 的有效产生者
DOI：
10.1002/hep.26182
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发表时间：
2013
期刊：
影响因子：
13.5
通讯作者：
Takehara T
中科院分区：
文献类型：
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作者：
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;Takehara T
白细胞介素（IL）-28 B（干扰素-λ [IFN]-λ3）基因多态性与丙型肝炎病毒（HCV）清除疗效密切相关。树突状细胞（DC）感知HCV并产生IFN，从而与HCV感染的肝细胞在诱导干扰素刺激基因（ISG）方面发挥某些协同作用。发现血液树突状细胞抗原3（BDCA 3）+DC在Toll样受体3（TLR 3）刺激后作为IFN-λ的产生者。因此，我们旨在阐明BDCA 3 + DC在抗HCV先天免疫中的作用。入组了70名健康受试者和20名肝肿瘤患者。与浆细胞样DC和髓样DC相比，BDCA 3 + DC用TLR激动剂、细胞培养的HCV（HCV 3）或用HCV/JFH-1转染的Huh 7.5.1细胞刺激。BDCA 3 + DC用抗CD 81抗体、内体酸化抑制剂、含TIR结构域的衔接子诱导干扰素β（TRIF）特异性抑制剂或紫外线照射的HC 1处理。通过亚型特异性酶联免疫吸附试验（ELISA）定量IL-29/IFN-λ1、IL-28 A/IFN-λ2和IL-28 B的含量。外周血单个核细胞（PBMC）中BDCA 3 + DC的频率极低，但在肝脏中较高。从PBMC或肝脏中回收的BDCA 3 + DC在用HCV 3或HCV转染的Huh 7.5.1刺激时释放大量IFN-λ。BDCA 3 + DC能够在共存的JFH-1-阳性Huh 7.5.1细胞中诱导ISG。用抗CD 81抗体、氯喹或巴弗洛霉素A1处理BDCA 3 +DCs减少了HCV-induced IL-28 B释放，而BDCA 3 +DCs在复制缺陷型HCV-induced时不产生IL-28 B。TRIF特异性抑制剂减少了HC 1刺激的BDCA 3 + DC的IL-28 B释放。在IL-28 B主要表达的健康受试者中，对HCV 6或JFH-1-Huh 7.5.1、BDCA 3 + DC的应答（rs 8099917，TT）比具有IL-28 B次要基因型（TG）的那些释放更多的IL-28 B。人BDCA 3 + DC倾向于在肝脏中积累，以CD 81-、内体-和TRIF-依赖性方式识别HCV，并产生大量的IL-28 B/IFN-λ3，其能力在具有IL-28 B主要基因型的受试者中上级。（肝脏学2013）
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. (HEPATOLOGY2013)