HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells.
Plasmacytoid dendritic cells (pDCs), the professional producers of type I interferons (IFN-alpha/beta), play a pivotal role in innate and adaptive immune responses against viral infections. Although functional impairment of circulating pDCs in chronic hepatitis B (CHB) patients has been reported previously, the mechanism responsible for these defects remains unclear. We hypothesize that HBsAg circulating in high amounts during HBV infection may interact with pDC and contribute to pDC dysfunction. In support of this hypothesis we show that pDCs treated with HBsAg secreted much less IFN-alpha than control pDCs. Furthermore, suppression is specific for TLR9, with no effects upon TLR7-mediated IFN-alpha secretion. HBsAg inhibited TLR9-mediated IRF-7 expression and nuclear translocation, which are important for induction of IFN-alpha gene transcription. HBsAg upregulated the SOCS-1 expression and bound to BDCA-2 receptors on the plasma membrane of pDCs, resulting in the inhibition of the IFN-alpha production. In conclusion, the above data suggested that HBsAg may directly interfere with the function of pDC through HBsAg-mediated upregulation of SOCS-1 expression and BDCA-2 ligation, which could partially explain how HBV evades the immune system to establish a persistent infection.
Xu
Yongfen
Y
Fudan University, China.
Hu
Yunwen
Y
Shi
Bisheng
B
Zhang
Xiaonan
X
Wang
Jiefei
J
Zhang
Zhanqing
Z
Shen
Fang
F
Zhang
Qin
Q
Sun
Shuhui
S
Yuan
Zhenghong
Z
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006514:Hepatitis B Surface Antigens / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism* / Q000819:agonists
C443299:CLEC4C protein, human; C526902:CpG ODN 2216; D006514:Hepatitis B Surface Antigens; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9