Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States.
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States.
Front Immunol. 2018 Dec 17;9:2922. doi: 10.3389/fimmu.2018.02922. eCollection 2018.
Recurrent viral diseases often occur after the viruses evade the hosts' immune system, by inducing exhaustion of antiviral T cells. In the present study, we found that functionally exhausted herpes simplex virus type 1 (HSV-1) -specific CD8 T cells, with elevated expression of lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that promotes T cell exhaustion, were frequent in symptomatic (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, following UV-B induced virus reactivation from latency the symptomatic wild-type (WT) B6 mice that developed increase virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific LAG-3CD8 T cells in both trigeminal ganglia (TG) and cornea. Moreover, a therapeutic blockade of LAG-3 immune checkpoint with antagonist antibodies combined with a therapeutic immunization with gB peptide immunodominant epitope of latently infected B6 mice significantly restored the quality and quantity of functional HSV-1 gB specific CD8 T cells in both TG and cornea and protected against UV-B induced recurrent corneal herpes infection and disease. In contrast to dysfunctional HSV-specific CD8 T cells from WT B6 mice, more functional HSV-specific CD8 T cells were detected in LAG-3 deficient mice and were associated with less UV-B induced recurrent corneal herpetic disease. Thus, the LAG-3 pathway plays a fundamental role in ocular herpes T cell immunopathology and provides an important immune checkpoint target that can synergizes with T cell-based therapeutic vaccines against symptomatic recurrent ocular herpes.
复发性病毒疾病经常在病毒逃避宿主免疫系统后发生，通过诱导抗病毒 T 细胞耗竭。在本研究中，我们发现具有高表达淋巴细胞激活基因-3（LAG-3）的功能耗竭单纯疱疹病毒 1（HSV-1）特异性 CD8 T 细胞在有反复发作性角膜疱疹病史的症状性（SYMP）患者中很常见，LAG-3 是一种促进 T 细胞耗竭的免疫检查点受体。同样，在 UV-B 诱导潜伏病毒重新激活后，出现病毒脱落增加和严重复发性角膜疱疹疾病的症状性野生型（WT）B6 小鼠中，在三叉神经节（TG）和角膜中也有更多耗竭的 HSV 特异性 LAG-3CD8 T 细胞。此外，用拮抗剂抗体阻断 LAG-3 免疫检查点，结合对潜伏感染 B6 小鼠进行 gB 肽免疫优势表位的治疗性免疫接种，可显著恢复 TG 和角膜中 HSV-1 gB 特异性 CD8 T 细胞的功能质量和数量，并防止 UV-B 诱导的复发性角膜疱疹感染和疾病。与 WT B6 小鼠的功能失调的 HSV 特异性 CD8 T 细胞相反，在 LAG-3 缺陷型小鼠中检测到更多的功能性 HSV 特异性 CD8 T 细胞，与较少的 UV-B 诱导的复发性角膜疱疹疾病相关。因此，LAG-3 途径在眼部疱疹 T 细胞免疫病理学中起着重要作用，并提供了一个重要的免疫检查点靶点，可与基于 T 细胞的治疗性疫苗协同作用，针对有症状的复发性眼部疱疹。
