Sakthivel Priya, Gereke Marcus, Bruder Dunja
Immune-Regulation Group, Helmholtz Center for Infection Research, Inhoffenstrasse 7, 38124-Braunschweig, Germany.
Rev Recent Clin Trials. 2012 Feb;7(1):10-23. doi: 10.2174/157488712799363262.
Programmed Death-1 (PD-1) is a negative regulator of T cell activation and proliferation that mediates suppressive action by binding to its ligands PD-L1 and PD-L2. The well-established immunosuppressive properties of PD-1/PD-L1 interaction resulting in the re-establishment of peripheral tolerance makes PD-1 an interesting target for therapeutic intervention in cancer patients. In addition to its relevance in tumor-specific immunity, recent studies demonstrate that PD-1 expression on T cells correlates with viral load in HIV and HCV infected patients and further identified PD-1 expression as a marker for exhausted virus-specific CD8+ T cells. In particular, PD-1+CD8+ T cells show impaired effector functions and PD-1 associated T cell exhaustion could be restored by blocking the PD-1/PD-L1 interaction. This results in recovery of virus-specific CD8+ T cell mediated immunity, suggesting that interrupting PD-1 signaling using an antagonistic antibody restores T-cell effector functions. Thus, immunotherapy based on the blockade of PD-1/PD-L1 interaction does not only result in breakdown of effector T-cell tolerance to tumor antigens, but in addition also represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic viral infections. In this review, we give a comprehensive overview about the immunological functions of PD-1 mediated signaling in T cells with special emphasis on its immune regulatory functions in the context of cancer and chronic viral infections. Moreover, we will summarize recent data obtained in animal models, in-vitro preclinical approaches in patients and their implementation in clinical trials for treating patients with cancer and chronic viral infections.
程序性死亡蛋白 1（PD-1）是 T 细胞活化和增殖的负调节因子，通过与其配体 PD-L1 和 PD-L2 结合来介导抑制作用。PD-1/PD-L1 相互作用所具有的已被充分证实的免疫抑制特性可导致外周耐受的重建，这使得 PD-1 成为癌症患者治疗干预的一个有吸引力的靶点。除了其在肿瘤特异性免疫中的相关性外，最近的研究表明，T 细胞上 PD-1 的表达与 HIV 和 HCV 感染患者的病毒载量相关，并进一步确定 PD-1 的表达是耗竭的病毒特异性 CD8+ T 细胞的一个标志物。特别是，PD-1+CD8+ T 细胞表现出效应功能受损，并且通过阻断 PD-1/PD-L1 相互作用可以恢复与 PD-1 相关的 T 细胞耗竭。这导致病毒特异性 CD8+ T 细胞介导的免疫恢复，表明使用拮抗抗体阻断 PD-1 信号传导可恢复 T 细胞效应功能。因此，基于阻断 PD-1/PD-L1 相互作用的免疫疗法不仅会导致效应 T 细胞对肿瘤抗原的耐受性破坏，而且此外还代表了一种有前景的治疗策略，用于重新激活病毒特异性效应 T 细胞以在慢性病毒感染中根除病原体。在这篇综述中，我们全面概述了 PD-1 介导的 T 细胞信号传导的免疫功能，特别强调了其在癌症和慢性病毒感染背景下的免疫调节功能。此外，我们将总结在动物模型、患者体外临床前研究方法中获得的最新数据，以及它们在治疗癌症和慢性病毒感染患者的临床试验中的应用情况。
