title: Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients.
abstract: Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-γ in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-β because blockade of TGF-β significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the α-smooth muscle actin (α-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the α-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-β treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells' anti-fibrosis capacity through a TGF-β-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity.
authors.affiliation: Department of Infectious Diseases, 302 Military Hospital of China-Peking University Teaching Hospital, Beijing, 100039, China.
authors.forename: Jijing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Research Center for Clinical &Translational Medicine, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Research Center for International Liver Disease, Beijing 302 Hospital, Beijing 100039, China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Research Center for Liver Failure, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Forensic Sursery Center, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, 88th Hospital of PLA, Taian, 271000, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Shang
authors.affiliation: Research Center for Clinical &Translational Medicine, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tu
authors.affiliation: Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Infectious Diseases, 302 Military Hospital of China-Peking University Teaching Hospital, Beijing, 100039, China.
authors.forename: Fu-Sheng
authors.initials: FS
authors.lastname: Wang
authors.affiliation: Research Center for Clinical &Translational Medicine, Beijing 302 Hospital, Beijing, 100039, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D057687:Emperipolesis / Q000235:genetics / Q000276:immunology; D005260:Female; D005355:Fibrosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000473:pathology; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000235:genetics*
chemical_list: D016212:Transforming Growth Factor beta; D007371:Interferon-gamma