Title |
Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8+ Cytolytic T Cell Responses
|
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Published in |
Immunity, February 2016
|
DOI | 10.1016/j.immuni.2016.01.018 |
Pubmed ID | |
Authors |
Alison Taylor, James A. Harker, Kittiphat Chanthong, Philip G. Stevenson, Elina I. Zuniga, Christopher E. Rudd |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 29% |
Russia | 1 | 14% |
United Kingdom | 1 | 14% |
Unknown | 3 | 43% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 5 | 71% |
Scientists | 1 | 14% |
Science communicators (journalists, bloggers, editors) | 1 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Japan | 1 | <1% |
Israel | 1 | <1% |
United States | 1 | <1% |
Unknown | 193 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 40 | 20% |
Student > Ph. D. Student | 37 | 19% |
Student > Master | 18 | 9% |
Student > Doctoral Student | 14 | 7% |
Student > Bachelor | 12 | 6% |
Other | 35 | 18% |
Unknown | 40 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Immunology and Microbiology | 47 | 24% |
Biochemistry, Genetics and Molecular Biology | 27 | 14% |
Agricultural and Biological Sciences | 25 | 13% |
Medicine and Dentistry | 25 | 13% |
Chemistry | 4 | 2% |
Other | 20 | 10% |
Unknown | 48 | 24% |