Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection.
Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection.
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DOI：
10.1038/nm.3831
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发表时间：
2015-04
期刊：
影响因子：
82.9
通讯作者：
Kaech SM
中科院分区：
文献类型：
--
作者：
Chen JH;Perry CJ;Tsui YC;Staron MM;Parish IA;Dominguez CX;Rosenberg DW;Kaech SM
超过10%的世界人口是慢性感染艾滋病毒，丙型肝炎病毒或乙型肝炎病毒，造成严重的疾病和死亡。这些病毒持续存在的部分原因是持续的抗原刺激导致病毒特异性细胞毒性T淋巴细胞（CTL）功能和存活的恶化。此外，抗病毒CTL通过上调抑制性受体如程序性细胞死亡1（PD-1）自主抑制其反应以限制免疫病理学。识别和阻断诱导CTL功能障碍的途径可能有助于清除慢性病毒感染。我们已经确定，前列腺素E2（PGE 2）受体EP 2和EP 4在慢性LCMV感染过程中上调病毒特异性CTL，并抑制CTL的存活和功能。我们发现，联合阻断PGE 2和PD-1信号传导在改善病毒控制和增加功能性病毒特异性CTL数量方面具有治疗作用。因此，PGE 2抑制既是独立的候选治疗靶点，也是PD-1阻断治疗HIV和其他慢性病毒感染的有前景的辅助疗法。
More than 10% of the world’s population is chronically infected with HIV, HCV or HBV, which cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as Programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate clearance of chronic viral infections. We have identified that the prostaglandin E2 (PGE2) receptors EP2 and EP4 are upregulated on virus-specific CTLs during chronic LCMV infection and suppress CTL survival and function. We showed that the combined blockade of PGE2 and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE2 inhibition is both independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for treatment of HIV and other chronic viral infections.