Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells
Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells
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DOI：
10.1074/jbc.ra119.010379
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发表时间：
2019-12-27
影响因子：
4.8
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Maeda, Natsumi;Maruhashi, Takumi;Okazaki, Taku
抑制性共受体程序性细胞死亡1(PD-1，Pdcd1)在自身免疫、抗癌免疫和抗感染免疫中起重要作用。针对PD-1的免疫疗法已经使癌症治疗发生了革命性的变化，并引发了各种改善癌症免疫疗法的试验。此外，正在进行广泛的试验，以增强PD-1的功能，以抑制有害的免疫反应。在这里，我们发现，天然和合成的糖皮质激素(GC)上调T细胞上的PD-1，而不改变其他辅助受体和细胞表面分子的表达水平。GC诱导的PD-1上调依赖于糖皮质激素受体介导的PD-1转录的反式激活。我们进一步发现，Pdcd1转录起始点上游2525bp的GC反应元件负责GC介导的反式激活。我们还观察到，在体内给予GCs显著上调肿瘤浸润性T细胞上PD-1的表达。通过分析不同PD-1表达的T细胞，我们直接证明了细胞表面PD-1的数量与其抑制作用有关。因此，GCs增强了PD-1抑制T细胞激活的能力，表明这种PD-1介导的抑制至少部分参与了GCs的抗炎和免疫抑制作用。鉴于PD-1在自身免疫调节中的关键作用，我们预计PD-1活性的增强可能为炎症性和自身免疫性疾病的管理提供一种有前途的治疗策略。我们目前的发现为寻求通过提高PD-1的表达水平来增强PD-1的抑制作用的策略提供了理论基础。
The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anticancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function to suppress harmful immune responses. Here we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell surface molecules. GC-induced up-regulation of PD-1 depended on transactivation of PD-1 transcription mediated through the glucocorticoid receptor. We further found that a GC response element 2525 bp upstream of the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level.