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STAT4-associated natural killer cell tolerance following liver transplantation.
- Source :
-
Gut [Gut] 2017 Feb; Vol. 66 (2), pp. 352-361. Date of Electronic Publication: 2016 Feb 17. - Publication Year :
- 2017
-
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.<br />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.<br />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.<br />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.<br />Competing Interests: Conflicts of Interest: None declared.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
- Subjects :
- Adult
Aged
Case-Control Studies
Cross-Sectional Studies
Down-Regulation
Female
HLA-C Antigens immunology
Hepatitis C, Chronic complications
Hepatitis C, Chronic immunology
Histocompatibility Testing
Humans
Ikaros Transcription Factor genetics
Killer Cells, Natural chemistry
Killer Cells, Natural metabolism
Lymphocyte Activation immunology
Male
MicroRNAs genetics
Middle Aged
Natural Cytotoxicity Triggering Receptor 1 analysis
Natural Cytotoxicity Triggering Receptor 3 analysis
Phenotype
Phosphorylation
STAT4 Transcription Factor metabolism
Immune Tolerance genetics
Killer Cells, Natural immunology
Liver Transplantation
Lymphocyte Activation genetics
STAT4 Transcription Factor genetics
STAT4 Transcription Factor immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 66
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 26887815
- Full Text :
- https://doi.org/10.1136/gutjnl-2015-309395