Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

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 virusinfected mice increased cytoplasmic hepatitis B virus DNA in hepatocytes and also increased serum hepatitis B surface antigen. The antiviral activity of CD8 + Tc ells 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. J. Leukoc. Biol. 98: 1071–1080; 2015.