Imperial College London
Alternate

DR JAMES A HARKER

Faculty of Medicine, National Heart & Lung Institute

Senior Lecturer in Respiratory Science
 
 
 
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Contact

 

+44 (0)20 7594 3171j.harker

 
 
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Location

 

360Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Taylor:2016:10.1016/j.immuni.2016.01.018,
author = {Taylor, A and Harker, JA and Chanthong, K and Stevenson, PG and Zuniga, EI and Rudd, CE},
doi = {10.1016/j.immuni.2016.01.018},
journal = {Immunity},
pages = {274--286},
title = {Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses},
url = {http://dx.doi.org/10.1016/j.immuni.2016.01.018},
volume = {44},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
AU  - Taylor,A
AU  - Harker,JA
AU  - Chanthong,K
AU  - Stevenson,PG
AU  - Zuniga,EI
AU  - Rudd,CE
DO  - 10.1016/j.immuni.2016.01.018
EP  - 286
PY  - 2016///
SN  - 1097-4180
SP  - 274
TI  - Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses
T2  - Immunity
UR  - http://dx.doi.org/10.1016/j.immuni.2016.01.018
UR  - http://hdl.handle.net/10044/1/32989
VL  - 44
ER  -
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