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Hepatology
Original article
STAT4-associated natural killer cell tolerance following liver transplantation
  1. K M Jamil1,
  2. T J Hydes2,
  3. K S Cheent1,
  4. S A Cassidy1,
  5. J A Traherne3,
  6. J Jayaraman3,
  7. J Trowsdale3,
  8. G J Alexander4,
  9. A-M Little5,
  10. H McFarlane5,
  11. M A Heneghan6,
  12. M A Purbhoo1,
  13. S I Khakoo1,2
  1. 1Department of Hepatology, Imperial College, London, UK
  2. 2Department of Hepatology, Southampton University, Southampton, UK
  3. 3Department of Pathology, University of Cambridge, Cambridge, UK
  4. 4Department of Hepatology, Addenbrookes Hospital, Cambridge, UK
  5. 5Histocompatibility and Immunogenetics Service, Gartnavel General Hospital, Glasgow, UK
  6. 6Institute of Liver Studies, Kings College Hospital London, London, UK
  1. Correspondence to Professor Salim I Khakoo, Henry Wellcome Laboratories, Mailpoint 811, Level E South Academic Block, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD. UK; S.I.Khakoo{at}soton.ac.uk

Abstract

Objective 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.

Design 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.

Results 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.

Conclusions 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.

  • LIVER TRANSPLANTATION
  • IMMUNOLOGY IN HEPATOLOGY
  • TOLERANCE
  • HEPATITIS C
  • RNA EXPRESSION

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/gutjnl-2015-309395

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    Footnotes

    • Contributors SIK, MAH and KMJ conceived and designed the study. MAH and GJA provided clinical data and patient access. KMJ and KSC collected samples and KMJ, JAT, HM, JJ and AL performed experiments. KMJ and SIK analysed and interpreted the data, and drafted the manuscript. KSC and MAP critically revised the manuscript for important intellectual content.

    • Funding This work was supported by grants from the Wellcome Trust to KMJ and SIK (092675/Z/10/Z).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval UK national research ethics committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Microarray data files are available on request to KMJ or SIK.