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STAT4-associated natural killer cell tolerance following liver transplantation

STAT4-associated natural killer cell tolerance following liver transplantation
STAT4-associated natural killer cell tolerance following liver transplantation
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)-? 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 IFN? 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.
0017-5749
1-11
Jamil, K.M.
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Hydes, T.J.
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Cheent, K.S.
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Cassidy, S.A.
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Traherne, J.A.
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Jayaraman, J.
b1ac431f-4120-4820-b1d2-e9a2d860ea98
Trowsdale, J.
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Alexander, G.J.
a487266f-690c-4910-b3d2-86aae406f4e8
Little, A.M.
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McFarlane, H.
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Heneghan, M.A.
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Purbhoo, M.A.
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Khakoo, S.I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Jamil, K.M.
47ddcf70-af79-4f48-b735-1260458fa9c6
Hydes, T.J.
c7744323-57ce-48fd-be8d-e299554297d9
Cheent, K.S.
9a9711a0-aad0-413d-a23f-a689ca547597
Cassidy, S.A.
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Traherne, J.A.
e284d977-a35d-469c-9a17-01dafae825f2
Jayaraman, J.
b1ac431f-4120-4820-b1d2-e9a2d860ea98
Trowsdale, J.
ec6c3b7d-a688-4375-a61b-dbff47669777
Alexander, G.J.
a487266f-690c-4910-b3d2-86aae406f4e8
Little, A.M.
7c14570e-3eee-4387-9fd6-c772e8970616
McFarlane, H.
d81bca3c-aee6-44c7-8195-67b7ffe31b88
Heneghan, M.A.
a2577bea-c4b3-48a5-913a-40a1848e5f04
Purbhoo, M.A.
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Khakoo, S.I.
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Jamil, K.M., Hydes, T.J., Cheent, K.S., Cassidy, S.A., Traherne, J.A., Jayaraman, J., Trowsdale, J., Alexander, G.J., Little, A.M., McFarlane, H., Heneghan, M.A., Purbhoo, M.A. and Khakoo, S.I. (2016) STAT4-associated natural killer cell tolerance following liver transplantation. Gut, 1-11. (doi:10.1136/gutjnl-2015-309395). (PMID:26887815)

Record type: Article

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)-? 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 IFN? 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.

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Accepted/In Press date: 20 October 2015
e-pub ahead of print date: 17 February 2016
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 390021
URI: https://eprints.soton.ac.uk/id/eprint/390021
ISSN: 0017-5749
PURE UUID: d1863eb5-1d10-4b1a-954c-8a6297c6aa9a

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Date deposited: 17 Mar 2016 12:11
Last modified: 09 Dec 2019 19:43

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Contributors

Author: K.M. Jamil
Author: T.J. Hydes
Author: K.S. Cheent
Author: S.A. Cassidy
Author: J.A. Traherne
Author: J. Jayaraman
Author: J. Trowsdale
Author: G.J. Alexander
Author: A.M. Little
Author: H. McFarlane
Author: M.A. Heneghan
Author: M.A. Purbhoo
Author: S.I. Khakoo

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