Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 98, Issue 6, Pages 1071-1080Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.4A0415-152R
Keywords
immunoregulation; mTOR; cytotoxic T lymphocyte
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Funding
- National Natural Science Foundation of China [81371789]
- Chinese Foundation for Hepatitis Prevention and Control [CFHPC20132133]
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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 thismammalian 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.
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