Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, USA.
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
Immunol Cell Biol. 2017 Nov;95(10):953-959. doi: 10.1038/icb.2017.62. Epub 2017 Aug 22.
Infection of the central nervous system (CNS) by murine polyomavirus (MuPyV), a persistent natural mouse pathogen, establishes brain-resident memory CD8 T cells (bT) that uniformly and chronically express programmed cell death protein 1 (PD-1) irrespective of the expression of α integrin CD103, a T cell marker. In contrast, memory antiviral CD8 T cells in the spleen are PD-1, despite viral loads being similar in both the brain and spleen during persistent infection. Repetitive antigen engagement is central to sustained PD-1 expression by T cells in chronic viral infections; however, recent evidence indicates that expression of inhibitory receptors, including PD-1, is part of the T differentiation program. Here we asked whether PD-1 expression by CD8 bT cells during persistent MuPyV encephalitis is antigen dependent. By transferring MuPyV-specific CD8 bT cells into the brains of naive mice and mice infected with cognate epitope-sufficient and -deficient MuPyVs, we demonstrate that antigen and inflammation are dispensable for PD-1 maintenance. In vitro and direct ex vivo analyses indicate that CD103 MuPyV-specific CD8 bT retain functional competence. We further show that the Pdcd-1 promoter of anti-MuPyV bT cells is epigenetically fixed in a demethylated state in the brain. In contrast, the PD-1 promoter of splenic antiviral memory CD8 T cells undergoes remethylation after being demethylated during acute infection. These data show that PD-1 expression is an intrinsic property of brain T cells in a persistent CNS viral infection.
中枢神经系统（CNS）感染鼠多瘤病毒（MuPyV），一种持续性天然鼠病原体，会产生大脑驻留记忆 CD8 T 细胞（bT），这些细胞均匀且慢性地表达程序性细胞死亡蛋白 1（PD-1），而不管 α 整合素 CD103的表达如何，CD103 是 T 细胞的一个标志物。相比之下，脾脏中的抗病毒记忆 CD8 T 细胞是 PD-1阳性的，尽管在持续性感染期间，大脑和脾脏中的病毒载量相似。重复抗原的结合是慢性病毒感染中 T 细胞持续表达 PD-1 的核心；然而，最近的证据表明，抑制性受体（包括 PD-1）的表达是 T 细胞分化程序的一部分。在这里，我们询问了 MuPyV 持续性脑炎期间 CD8 bT 细胞的 PD-1 表达是否依赖于抗原。通过将 MuPyV 特异性 CD8 bT 细胞转移到幼稚小鼠和感染同源表位充足和不足 MuPyV 的小鼠的大脑中，我们证明了抗原和炎症对于 PD-1 的维持是可有可无的。体外和直接的体外分析表明，CD103 MuPyV 特异性 CD8 bT 保持功能能力。我们进一步表明，抗 MuPyV bT 细胞的 Pdcd-1 启动子在大脑中处于去甲基化的稳定状态。相比之下，脾脏中的抗病毒记忆 CD8 T 细胞的 PD-1 启动子在急性感染期间去甲基化后会重新甲基化。这些数据表明，PD-1 表达是持续性中枢神经系统病毒感染中大脑 T 细胞的固有特性。
