title: STAT4-associated natural killer cell tolerance following liver transplantation.
abstract: Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype.
  
  
  
  Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing.
  
  
  
  NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)-γ secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV.
  
  
  
  LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease.
authors.affiliation: Department of Hepatology, Imperial College, London, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Jamil
authors.affiliation: Department of Hepatology, Southampton University, Southampton, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Hydes
authors.affiliation: Department of Hepatology, Imperial College, London, UK.
authors.forename: K S
authors.initials: KS
authors.lastname: Cheent
authors.affiliation: Department of Hepatology, Imperial College, London, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Cassidy
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Traherne
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Jayaraman
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Trowsdale
authors.affiliation: Department of Hepatology, Addenbrookes Hospital, Cambridge, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Alexander
authors.affiliation: Histocompatibility and Immunogenetics Service, Gartnavel General Hospital, Glasgow, UK.
authors.forename: A-M
authors.initials: AM
authors.lastname: Little
authors.affiliation: Histocompatibility and Immunogenetics Service, Gartnavel General Hospital, Glasgow, UK.
authors.forename: H
authors.initials: H
authors.lastname: McFarlane
authors.affiliation: Institute of Liver Studies, Kings College Hospital London, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Heneghan
authors.affiliation: Department of Hepatology, Imperial College, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Purbhoo
authors.affiliation: Department of Hepatology, Imperial College, London, UK.|Department of Hepatology, Southampton University, Southampton, UK.
authors.forename: S I
authors.initials: SI
authors.lastname: Khakoo
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D005260:Female; D015236:HLA-C Antigens / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000150:complications / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D016031:Liver Transplantation; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000032:analysis; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000032:analysis; D010641:Phenotype; D010766:Phosphorylation; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: D015236:HLA-C Antigens; C111431:IKZF2 protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D051740:Ikaros Transcription Factor
keywords: HEPATITIS C; IMMUNOLOGY IN HEPATOLOGY; LIVER TRANSPLANTATION; RNA EXPRESSION; TOLERANCE