Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation.
Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation.
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DOI：
10.1126/scisignal.2002796
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发表时间：
2012-06-26
影响因子：
7.3
通讯作者：
Boussiotis VA
中科院分区：
文献类型：
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作者：
Patsoukis N;Brown J;Petkova V;Liu F;Li L;Boussiotis VA
受体程序性死亡 1 (PD-1) 抑制 T 细胞增殖，在抑制自身反应性 T 细胞中发挥关键作用，并且还会影响抗病毒和抗肿瘤反应。为了确定 PD-1 信号传导如何抑制 T 细胞增殖，我们使用人 CD4+ T 细胞来检查 PD-1 信号传导对细胞周期分子控制的影响。泛素连接酶 SCFSkp2 会降解 p27kip1（一种细胞周期蛋白依赖性激酶 (Cdks) 抑制剂），而 PD-1 通过抑制 SKP2（编码该泛素连接酶的一个成分）的转录来阻断细胞周期进展至 G1 期。因此，在通过PD-1刺激的T细胞中，Cdk没有被激活，并且两个关键的Cdk底物没有被磷酸化。 PD-1 的激活抑制视网膜母细胞瘤基因产物的磷酸化，从而抑制 E2F 靶基因的表达。 PD-1 还抑制转录因子 Smad3 的磷酸化，从而增加其活性。这些事件通过增加 G1 期抑制剂 p15INK4 的丰度并抑制 Cdk 激活磷酸酶 Cdc25A，在细胞周期中诱导额外的抑制检查点。 PD-1 通过抑制磷酸肌醇 3 激酶 - Akt 和 Ras - 丝裂原激活和细胞外信号调节激酶激酶 (MEK) - 细胞外信号调节激酶 (ERK) 信号传导来抑制 SKP2 转录。将细胞暴露于促进增殖的细胞因子白介素-2 中可以恢复 MEK-ERK 信号传导的激活，但不能恢复 Akt 信号传导的激活，并且仅部分恢复 SKP2 的表达。因此，PD-1 通过影响细胞周期的多个调节因子来阻断细胞周期进程和 T 淋巴细胞的增殖。
The receptor programmed death 1 (PD-1) inhibits T cell proliferation and plays a critical role in suppressing self-reactive T cells, and it also compromises antiviral and antitumor responses. To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4+ T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle. The ubiquitin ligase SCFSkp2 degrades p27kip1, an inhibitor of cyclin-dependent kinases (Cdks), and PD-1 blocked cell cycle progression through the G1 phase by suppressing transcription of SKP2, which encodes a component of this ubiquitin ligase. Thus, in T cells stimulated through PD-1, Cdks were not activated, and two critical Cdk substrates were not phosphorylated. Activation of PD-1 inhibited phosphorylation of the retinoblastoma gene product, which suppressed expression of E2F target genes. PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G1 phase inhibitor p15INK4 and repressing the Cdk-activating phosphatase Cdc25A. PD-1 suppressed SKP2 transcription by inhibiting phosphoinositide 3-kinase–Akt and Ras–mitogen-activated and extracellular signal–regulated kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) signaling. Exposure of cells to the proliferation-promoting cytokine interleukin-2 restored activation of MEK-ERK signaling, but not Akt signaling, and only partially restored SKP2 expression. Thus, PD-1 blocks cell cycle progression and proliferation of T lymphocytes by affecting multiple regulators of the cell cycle.