Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Immunity. 2011 Sep 23;35(3):400-12. doi: 10.1016/j.immuni.2011.06.015.
Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8(+) T cell differentiation. During acute infection, naive to effector CD8(+) T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 regulatory region was completely demethylated in exhausted CD8(+) T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.
功能耗竭的 T 细胞高表达 PD-1 抑制性受体，阻断 PD-1 信号通路的疗法有望解决慢性病毒感染和癌症。通过利用人类和鼠类的急性和慢性病毒感染系统，我们分析了 CD8+T 细胞分化过程中 PD-1 表达的表观遗传调控。在急性感染过程中，从初始状态到效应状态的 CD8+T 细胞分化伴随着 PDcd1 基因座的 DNA 甲基化短暂丢失，这与 T 细胞受体信号的持续时间和强度直接相关。进一步分化为功能记忆细胞伴随着 Pdcd1 再甲基化，为 PD-1 表达的调控提供了一种适应性程序。相比之下，在耗竭的 CD8+T 细胞中，Pdcd1 调控区完全去甲基化，即使病毒滴度降低，仍保持非甲基化状态。这种 DNA 再甲基化的缺失使 Pdcd1 基因座处于快速表达的准备状态，可能为抗病毒功能的过早终止提供信号。
