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PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-12-31 , DOI: 10.1016/j.molcel.2019.12.012 Kenji Shimizu 1 , Daisuke Sugiura 1 , Il-Mi Okazaki 1 , Takumi Maruhashi 1 , Yujiro Takegami 2 , Chaoyang Cheng 2 , Soichi Ozaki 2 , Taku Okazaki 1
Molecular Cell ( IF 14.5 ) Pub Date : 2019-12-31 , DOI: 10.1016/j.molcel.2019.12.012 Kenji Shimizu 1 , Daisuke Sugiura 1 , Il-Mi Okazaki 1 , Takumi Maruhashi 1 , Yujiro Takegami 2 , Chaoyang Cheng 2 , Soichi Ozaki 2 , Taku Okazaki 1
Affiliation
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Targeted blockade of programmed cell death 1 (PD-1), an immune-checkpoint receptor that inhibits T cell activation, provides clinical benefits in various cancers. However, how PD-1 modulates gene expression in T cells remains enigmatic. Here we investigated how PD-1 affects transcriptome changes induced by T cell receptor (TCR) activation. Intriguingly, we identified a huge variance in PD-1 sensitivity among TCR-inducible genes. When we quantified the half maximal effective concentration (EC50) as the relationship between change in gene expression and TCR signal strength, we found that genes associated with survival and proliferation were efficiently expressed upon TCR activation and resistant to PD-1-mediated inhibition. Conversely, genes encoding cytokines and effector molecules were expressed less efficiently and sensitive to PD-1-mediated inhibition. We further demonstrated that transcription factor binding motifs and CpG frequency in the promoter region affect EC50 and thus the PD-1 sensitivity of genes. Our findings explain how PD-1, dependent on the TCR signal strength, calibrates cellular transcriptomes to shape functional properties of T cell populations.
中文翻译：
PD-1响应T细胞活化对细胞转录组进行定性控制。
靶向阻断程序性细胞死亡1（PD-1）是一种抑制T细胞活化的免疫检查点受体，可在多种癌症中提供临床益处。然而，PD-1如何调节T细胞中的基因表达仍然是个谜。在这里，我们研究了PD-1如何影响T细胞受体（TCR）激活诱导的转录组变化。有趣的是，我们发现了TCR诱导基因中PD-1敏感性的巨大差异。当我们将半数最大有效浓度（EC50）量化为基因表达变化与TCR信号强度之间的关系时，我们发现与生存和增殖相关的基因在TCR激活后能有效表达，并且对PD-1介导的抑制具有抗性。反过来，编码细胞因子和效应分子的基因表达效率较低，并且对PD-1介导的抑制作用敏感。我们进一步证明了转录因子结合基序和启动子区域中的CpG频率影响EC50，从而影响基因的PD-1敏感性。我们的发现解释了PD-1如何依赖于TCR信号强度来校准细胞转录组以塑造T细胞群体的功能特性。
更新日期：2020-01-08
中文翻译：
PD-1响应T细胞活化对细胞转录组进行定性控制。
靶向阻断程序性细胞死亡1（PD-1）是一种抑制T细胞活化的免疫检查点受体，可在多种癌症中提供临床益处。然而，PD-1如何调节T细胞中的基因表达仍然是个谜。在这里，我们研究了PD-1如何影响T细胞受体（TCR）激活诱导的转录组变化。有趣的是，我们发现了TCR诱导基因中PD-1敏感性的巨大差异。当我们将半数最大有效浓度（EC50）量化为基因表达变化与TCR信号强度之间的关系时，我们发现与生存和增殖相关的基因在TCR激活后能有效表达，并且对PD-1介导的抑制具有抗性。反过来，编码细胞因子和效应分子的基因表达效率较低，并且对PD-1介导的抑制作用敏感。我们进一步证明了转录因子结合基序和启动子区域中的CpG频率影响EC50，从而影响基因的PD-1敏感性。我们的发现解释了PD-1如何依赖于TCR信号强度来校准细胞转录组以塑造T细胞群体的功能特性。
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