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CD81/CD9 tetraspanins aid plasmacytoid dendritic cells in recognition of hepatitis C virus–infected cells and induction of interferon‐alpha
Author(s) -
Zhang Shuye,
Kodys Karen,
Babcock Gregory J.,
Szabo Gyongyi
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25827
Subject(s) - cd81 , virology , plasmacytoid dendritic cell , hepatitis c virus , biology , interferon , dendritic cell , immunology , virus , immune system
Recognition of hepatitis C virus (HCV)‐infected hepatocyes and interferon (IFN) induction are critical in antiviral immune response. We hypothesized that cell‐cell contact between plasmacytoid dendritic cells (pDCs) and HCV‐infected cells was required for IFN‐α induction through the involvement of cell‐surface molecules. Coculture of human peripheral blood mononuclear cells (PBMCs) with genotype 1a full‐length (FL) HCV genomic replicon cells or genotype 2a Japanese fulminant hepatitis type 1 (JFH‐1) virus‐infected hepatoma cells (JFH‐1), and not with uninfected hepatoma cells (Huh7.5), induced IFN‐α production. Depletion of pDCs from PBMCs attenuated IFN‐α release, and purified pDCs produced high levels of IFN‐α after coculture with FL replicons or JFH‐1‐infected cells. IFN‐α induction by HCV‐containing hepatoma cells required viral replication, direct cell‐cell contact with pDCs, and receptor‐mediated endocytosis. We determined that the tetraspanin proteins, CD81 and CD9, and not other HCV entry receptors, were required for IFN‐α induction in pDCs by HCV‐infected hepatoma cells. Disruption of cholesterol‐rich membrane microdomains, the localization site of CD81, or inhibition of the CD81 downstream molecule, Rac GTPase, inhibited IFN‐α production. IFN‐α induction involved HCV RNA and Toll‐like receptor (TLR) 7. IFN‐α production by HCV‐infected hepatoma cells was decreased in pDCs from HCV‐infected patients, compared to healthy controls. We found that preexposure of healthy PBMCs to HCV viral particles attenuated IFN‐α induction by HCV‐infected hepatoma cells or TLR ligands, and this inhibitory effect could be prevented by an anti‐HCV envelope glycoprotein 2–blocking antibody. Conclusion: Our novel data show that recognition of HCV‐infected hepatoma cells by pDCs involves CD81‐ and CD9‐associated membrane microdomains and induces potent IFN‐α production. (H EPATOLOGY 2013;58:940–949)