Acute viral infection or vaccination generates highly functional memory CD8 T cells following the Ag resolution. In contrast, persistent antigenic stimulation in chronic viral infection and cancer leads to a state of T-cell dysfunction termed T-cell exhaustion. We and other have recently identified a novel subset of exhausted CD8 T cells that act as stem cells for maintaining virus-specific CD8 T cells in a mouse model of chronic lymphocytic choriomeningitis virus infection. This stem cell-like CD8 T-cell subset has been also observed in both mouse and human tumor models. Most importantly, in both chronic viral infection and tumor models, the proliferative burst of Ag-specific CD8 T cells driven by PD-1-directed immunotherapy comes exclusively from this stem cell-like CD8 T-cell subset. Therefore, a better understanding of the mechanisms how CD8 T-cell subsets are regulated during chronic viral infection and cancer is required to improve the current immunotherapies that restore the function of exhausted CD8 T cells. In this review, we discuss the differentiation of virus-specific CD8 T cells during chronic viral infection, the characteristics and function of CD8 T-cell subsets, and the therapeutic intervention of PD-1-directed immunotherapy in cancer.

中文翻译：

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重新定义 T 细胞耗竭：子集、功能和调节

急性病毒感染或疫苗接种会在 Ag 分辨率后产生高功能记忆 CD8 T 细胞。相反，慢性病毒感染和癌症中的持续抗原刺激会导致 T 细胞功能障碍状态，称为 T 细胞衰竭。我们和其他人最近发现了一个新的耗尽 CD8 T 细胞亚群，它们充当干细胞，用于在慢性淋巴细胞脉络丛脑膜炎病毒感染的小鼠模型中维持病毒特异性 CD8 T 细胞。在小鼠和人类肿瘤模型中也观察到了这种干细胞样 CD8 T 细胞亚群。最重要的是，在慢性病毒感染和肿瘤模型中，由 PD-1 定向免疫疗法驱动的 Ag 特异性 CD8 T 细胞的增殖爆发完全来自这种干细胞样 CD8 T 细胞亚群。所以，需要更好地了解 CD8 T 细胞亚群在慢性病毒感染和癌症期间如何调节的机制，以改善当前恢复耗竭 CD8 T 细胞功能的免疫疗法。在这篇综述中，我们讨论了慢性病毒感染期间病毒特异性 CD8 T 细胞的分化、CD8 T 细胞亚群的特征和功能，以及 PD-1 定向免疫疗法在癌症中的治疗干预。