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Amphiregulin promotes the immunosuppressive activity of intrahepatic CD 4 + regulatory T cells to impair CD 8 + T‐cell immunity against hepatitis B virus infection
Author(s) -
Dai Kai,
Huang Ling,
Chen Jing,
Yang Lihua,
Gong Zuojiong
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12400
Subject(s) - amphiregulin , hepatitis b virus , cd8 , immunology , biology , cytokine , hepatocellular carcinoma , t cell , cancer research , immune system , virology , epidermal growth factor receptor , virus , receptor , biochemistry
Summary Hepatitis B virus ( HBV ) infection causes liver diseases and hepatocellular carcinoma. Immunotolerance in HBV ‐infected patients is one of the factors that incur failure of HBV clearance and persistent HBV amplification. However, the mechanisms underlying immunotolerance after HBV infection are yet to be thoroughly understood. Using a novel HBV mouse model, we found for the first time that epidermal growth factor receptor ( EGFR ) is up‐regulated on intrahepatic regulatory T (Treg) cells in HBV ‐infected mouse livers. The EGFR ‐positive Treg cells are more immunosuppressive than EGFR ‐negative Treg cells, demonstrated by higher expression of immunosuppressive cytokines and robust inhibition of CD 8 + T‐cell proliferation in vitro . Furthermore, EGFR ‐positive Treg cells potently restrain CD 8 + T‐cell‐mediated anti‐viral activity, leading to higher HBV burden in hepatocytes. Amphiregulin, a cytokine of the EGF family, is significantly up‐regulated in HBV ‐infected livers, but the cellular sources of amphiregulin are still elusive. Amphiregulin promotes the immunosuppressive activity of EGFR ‐positive Treg cells in vitro , so as to profoundly inhibit production of anti‐viral components in CD 8 + T cells. Taken together, our discovery elucidated a novel mechanism contributing to immunotolerance and viral amplification after HBV infection. Our study may provide new clues for developing therapeutic strategies against HBV infection.