title: Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection.
abstract: Hepatitis B virus is a major cause of chronic liver inflammation worldwide. Innate and adaptive immune responses work together to restrain or eliminate hepatitis B virus in the liver. Compromised or failed adaptive immune response results in persistent virus replication and spread. How to promote antiviral immunity is a research focus for hepatitis B virus prevention and therapy. In this study, we investigated the role of macrophages in the regulation of antiviral immunity. We found that F4/80(+)CD206(+)CD80(lo/+) macrophages were a particular hepatic macrophage subset that expressed amphiregulin in our mouse hepatitis B virus infection model. CD206(+) macrophage-derived amphiregulin promoted the immunosuppressive activity of intrahepatic regulatory T cells, demonstrated by higher expression of CTLA-4, ICOS, and CD39, as well as stronger inhibition of antiviral function of CD8(+) T cells. Amphiregulin-neutralizing antibody diminished the effect of CD206(+) macrophages on regulatory T cells. In addition, we found that CD206(+) macrophage-derived amphiregulin activated mammalian target of rapamycin signaling in regulatory T cells, and this mammalian target of rapamycin activation was essential for promotion of regulatory T cell activity by CD206(+) macrophages. Adoptive transfer of CD206(+) macrophages into hepatitis B virus-infected mice increased cytoplasmic hepatitis B virus DNA in hepatocytes and also increased serum hepatitis B surface antigen. The antiviral activity of CD8(+) T cells was decreased after macrophage transfer. Therefore, our research indicated that amphiregulin produced by CD206(+) macrophages plays an important role in modulating regulatory T cell function and subsequently restrains the antiviral activity of CD8(+) T cells. Our study offers new insights into the immunomodulation in hepatitis B virus infection.
authors.affiliation: *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China daikai@whu.edu.cn.
authors.forename: Kai
authors.initials: K
authors.lastname: Dai
authors.affiliation: *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Sun
authors.affiliation: *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.affiliation: *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China.
authors.forename: Zuojiong
authors.initials: Z
authors.lastname: Gong
mesh_terms: D066258:Amphiregulin; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001081:Apyrase / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D004195:Disease Models, Animal; D066255:EGF Family of Proteins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006509:Hepatitis B / Q000276:immunology* / Q000473:pathology; D006515:Hepatitis B virus / Q000276:immunology*; D007108:Immune Tolerance; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology*; D051379:Mice; D011956:Receptors, Cell Surface / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology
chemical_list: D066258:Amphiregulin; D015703:Antigens, CD; C587849:Areg protein, mouse; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D066255:EGF Family of Proteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001081:Apyrase; C067869:CD39 antigen
keywords: cytotoxic T lymphocyte; immunoregulation; mTOR