Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California, Irvine, Irvine, CA 92697.
Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California, Irvine, Irvine, CA 92697;
J Immunol. 2020 Jul 15;205(2):454-468. doi: 10.4049/jimmunol.2000131. Epub 2020 Jun 15.
A large proportion of the world's population harbors latent HSV type 1 (HSV-1). Cross-talk between antiviral CD8 T cells and HSV-1 appear to control latency/reactivation cycles. We found that compared with healthy asymptomatic individuals, in symptomatic (SYMP) patients, the CD8 T cells with the same HLA-A0201-restricted HSV-1 epitope specificities expressed multiple genes and proteins associated to major T cell exhaustion pathways and were dysfunctional. Blockade of immune checkpoints with anti-LAG-3 and anti-PD-1 antagonist mAbs synergistically restored the frequency and function of antiviral CD8 T cells, both 1) ex vivo, in SYMP individuals and SYMP HLA-A0201 transgenic mice; and 2) in vivo in HSV-1-infected SYMP HLA-A*0201 transgenic mice. This was associated with a significant reduction in virus reactivation and recurrent ocular herpetic disease. These findings confirm antiviral CD8 T cell exhaustion during SYMP herpes infection and pave the way to targeting immune checkpoints to combat recurrent ocular herpes.
世界上很大一部分人口携带潜伏的单纯疱疹病毒 1 型（HSV-1）。抗病毒 CD8 T 细胞与 HSV-1 之间的串扰似乎控制着潜伏期/再激活循环。我们发现，与健康无症状个体相比，在有症状（SYMP）患者中，具有相同 HLA-A0201 限制的 HSV-1 表位特异性的 CD8 T 细胞表达了多个与主要 T 细胞耗竭途径相关的基因和蛋白质，并且功能失调。用抗 LAG-3 和抗 PD-1 拮抗剂单克隆抗体阻断免疫检查点可协同恢复抗病毒 CD8 T 细胞的频率和功能，这在 1）SYMP 个体和 SYMP HLA-A0201 转基因小鼠的体外实验中；和 2）在 HSV-1 感染的 SYMP HLA-A*0201 转基因小鼠的体内实验中。这与病毒再激活和复发性眼部疱疹疾病的显著减少相关。这些发现证实了 SYMP 疱疹感染期间抗病毒 CD8 T 细胞耗竭，并为靶向免疫检查点以对抗复发性眼部疱疹铺平了道路。
