期刊
IMMUNITY
卷 44, 期 2, 页码 274-286出版社
CELL PRESS
DOI: 10.1016/j.immuni.2016.01.018
关键词
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类别
资金
- Wellcome Trust [092627/Z/10/Z]
- Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute (New York)
- Leukemia and Lymphoma Society Scholar Award
- NIH [AI081923]
- Wellcome Trust [092627/Z/10/Z] Funding Source: Wellcome Trust
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 alpha and beta) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key up-stream 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.
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