PMID- 26887815
OWN - NLM
STAT- MEDLINE
DCOM- 20170710
LR  - 20220129
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Print)
IS  - 0017-5749 (Linking)
VI  - 66
IP  - 2
DP  - 2017 Feb
TI  - STAT4-associated natural killer cell tolerance following liver transplantation.
PG  - 352-361
LID - 10.1136/gutjnl-2015-309395 [doi]
AB  - 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)-gamma 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 IFNgamma 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.
CI  - 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/.
FAU - Jamil, K M
AU  - Jamil KM
AD  - Department of Hepatology, Imperial College, London, UK.
FAU - Hydes, T J
AU  - Hydes TJ
AD  - Department of Hepatology, Southampton University, Southampton, UK.
FAU - Cheent, K S
AU  - Cheent KS
AD  - Department of Hepatology, Imperial College, London, UK.
FAU - Cassidy, S A
AU  - Cassidy SA
AD  - Department of Hepatology, Imperial College, London, UK.
FAU - Traherne, J A
AU  - Traherne JA
AD  - Department of Pathology, University of Cambridge, Cambridge, UK.
FAU - Jayaraman, J
AU  - Jayaraman J
AD  - Department of Pathology, University of Cambridge, Cambridge, UK.
FAU - Trowsdale, J
AU  - Trowsdale J
AD  - Department of Pathology, University of Cambridge, Cambridge, UK.
FAU - Alexander, G J
AU  - Alexander GJ
AD  - Department of Hepatology, Addenbrookes Hospital, Cambridge, UK.
FAU - Little, A-M
AU  - Little AM
AD  - Histocompatibility and Immunogenetics Service, Gartnavel General Hospital, 
      Glasgow, UK.
FAU - McFarlane, H
AU  - McFarlane H
AD  - Histocompatibility and Immunogenetics Service, Gartnavel General Hospital, 
      Glasgow, UK.
FAU - Heneghan, M A
AU  - Heneghan MA
AD  - Institute of Liver Studies, Kings College Hospital London, London, UK.
FAU - Purbhoo, M A
AU  - Purbhoo MA
AD  - Department of Hepatology, Imperial College, London, UK.
FAU - Khakoo, S I
AU  - Khakoo SI
AD  - Department of Hepatology, Imperial College, London, UK.
AD  - Department of Hepatology, Southampton University, Southampton, UK.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - MR/L016567/1/MRC_/Medical Research Council/United Kingdom
GR  - 092675/Z/10/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160217
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (HLA-C Antigens)
RN  - 0 (IKZF2 protein, human)
RN  - 0 (MIRN155 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (NCR1 protein, human)
RN  - 0 (NCR3 protein, human)
RN  - 0 (Natural Cytotoxicity Triggering Receptor 1)
RN  - 0 (Natural Cytotoxicity Triggering Receptor 3)
RN  - 0 (STAT4 Transcription Factor)
RN  - 0 (STAT4 protein, human)
RN  - 148971-36-2 (Ikaros Transcription Factor)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Case-Control Studies
MH  - Cross-Sectional Studies
MH  - Down-Regulation
MH  - Female
MH  - HLA-C Antigens/immunology
MH  - Hepatitis C, Chronic/complications/immunology
MH  - Histocompatibility Testing
MH  - Humans
MH  - Ikaros Transcription Factor/genetics
MH  - Immune Tolerance/*genetics
MH  - Killer Cells, Natural/chemistry/*immunology/metabolism
MH  - *Liver Transplantation
MH  - Lymphocyte Activation/*genetics/immunology
MH  - Male
MH  - MicroRNAs/genetics
MH  - Middle Aged
MH  - Natural Cytotoxicity Triggering Receptor 1/analysis
MH  - Natural Cytotoxicity Triggering Receptor 3/analysis
MH  - Phenotype
MH  - Phosphorylation
MH  - STAT4 Transcription Factor/*genetics/*immunology/metabolism
PMC - PMC5284485
OTO - NOTNLM
OT  - HEPATITIS C
OT  - IMMUNOLOGY IN HEPATOLOGY
OT  - LIVER TRANSPLANTATION
OT  - RNA EXPRESSION
OT  - TOLERANCE
COIS- Conflicts of Interest: None declared.
EDAT- 2016/02/19 06:00
MHDA- 2017/07/14 06:00
PMCR- 2017/01/31
CRDT- 2016/02/19 06:00
PHST- 2015/02/15 00:00 [received]
PHST- 2015/09/29 00:00 [revised]
PHST- 2015/10/20 00:00 [accepted]
PHST- 2016/02/19 06:00 [pubmed]
PHST- 2017/07/14 06:00 [medline]
PHST- 2016/02/19 06:00 [entrez]
PHST- 2017/01/31 00:00 [pmc-release]
AID - gutjnl-2015-309395 [pii]
AID - 10.1136/gutjnl-2015-309395 [doi]
PST - ppublish
SO  - Gut. 2017 Feb;66(2):352-361. doi: 10.1136/gutjnl-2015-309395. Epub 2016 Feb 17.