Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice.
A fraction of HBV carriers have a risk to develop liver cancer. Because liver possesses a strong regeneration capability, surgical resection of cancerous liver or transplantation with healthy liver is an alternate choice for HBV-caused hepatocarcinoma therapy. How HBV infection affects the regeneration of hepatectomized or transplanted liver remains elusive. We report that partial hepatectomy (PHx)-induced liver regeneration was reduced in HBV transgenic (HBV-tg) mice, a model of human HBV infection. PHx markedly triggered natural killer T (NKT) cell accumulation in the hepatectomized livers of HBV-tg mice, simultaneously with enhanced interferon gamma (IFN-gamma) production and CD69 expression on hepatic NKT cells at the early stage of liver regeneration. The impairment of liver regeneration in HBV-tg mice was largely ameliorated by NKT cell depletion, but not by natural killer (NK) cell depletion. Blockage of CD1d-NKT cell interaction considerably alleviated NKT cell activation and their inhibitory effect on regenerating hepatocytes. Neutralization of IFN-gamma enhanced bromodeoxyuridine incorporation in HBV-tg mice after PHx, and IFN-gamma mainly induced hepatocyte cell cycle arrest. Adoptive transfer of NKT cells from regenerating HBV-tg liver, but not from normal mice, could inhibit liver regeneration in recipient mice.


CONCLUSIONS
Activated NKT cells negatively regulate liver regeneration of HBV-tg mice in the PHx model.
Dong
Zhongjun
Z
Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei, Anhui 230027, China.
Zhang
Jianhong
J
Sun
Rui
R
Wei
Haiming
H
Tian
Zhigang
Z
D019264:Adoptive Transfer; D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D004195:Disease Models, Animal; D006498:Hepatectomy; D006509:Hepatitis B / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008115:Liver Regeneration / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000276:immunology
D018949:Antigens, CD1; D055610:Antigens, CD1d; D000998:Antiviral Agents; C526877:CD1D protein, human; D007371:Interferon-gamma