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首页> 外文期刊>Immunity >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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Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses

机译：糖原合酶激酶3失活驱动共受体PD-1的T-bet介导下调，以增强CD8（+）细胞溶解性T细胞反应。

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摘要

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.
机译：尽管共受体PD-1在T细胞免疫中很重要，但尚未定义调节PD-1表达的上游信号通路。糖原合酶激酶3（GSK-3，亚型α和β）是一种丝氨酸-苏氨酸激酶，与细胞过程有关。在这里，我们确定GSK-3为调节CD8（+）T细胞中PD-1表达的关键上游激酶。 GSK-3 siRNA下调或受小分子抑制，阻止PD-1表达，导致CD8（+）细胞毒性T淋巴细胞（CTL）功能增加。从机制上讲，GSK-3失活增加了Tbx21转录，促进了增强的T-bet表达并随后抑制了CD8（+）CTL中Pdcd1（编码PD-1）的转录。在小鼠中注射GSK-3抑制剂可提高体内CD8（+）OT-1 CTL功能以及清除鼠γ-疱疹病毒68和淋巴细胞性脉络膜脑膜炎克隆13并逆转T细胞衰竭。我们的发现将GSK-3识别为PD-1表达的调节剂，并证明了GSK-3抑制剂在免疫疗法中调节PD-1的适用性。

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