Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA.
Division of Basic and Clinical Immunology, Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, USA.
J Virol. 2019 Feb 5;93(4). doi: 10.1128/JVI.01882-18. Print 2019 Feb 15.
A large proportion of the world population harbors herpes simplex virus 1 (HSV-1), a major cause of infectious corneal blindness. HSV-specific CD8 T cells protect from herpesvirus infection and disease. However, the genomic, phenotypic, and functional characteristics of CD8 T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who, despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8 T cells, sharing the same HSV-1 epitope specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and nonprotected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease, using the high-throughput digital NanoString nCounter system and flow cytometry. Interestingly, our results demonstrated that memory CD8 T cells from ASYMP individuals expressed a unique set of genes involved in expansion and survival, type I interferon (IFN-I), and JAK/STAT pathways. Frequent multifunctional HSV-specific effector memory CD62L CD44 CD8 T cells were detected in ASYMP individuals compared to more of monofunctional central memory CD62L CD44 CD8 T cells in SYMP individuals. Shedding light on the genotype, phenotype, and function of antiviral CD8 T cells from "naturally protected" ASYMP individuals will help design future T-cell-based ocular herpes immunotherapeutic vaccines. A staggering number of the world population harbors herpes simplex virus 1 (HSV-1) potentially leading to blinding recurrent herpetic disease. While the majority are asymptomatic (ASYMP) individuals who never experienced any recurrent herpetic disease, symptomatic (SYMP) individuals have a history of numerous episodes of recurrent ocular herpetic disease. This study elucidates the phenotype, the effector function, and the gene signatures of memory CD8 T-cell populations associated with protection seen in ASYMP individuals. Frequent multifunctional HSV-specific effector memory CD8 T cells were detected in ASYMP individuals. In contrast, nonprotected SYMP individuals had more central memory CD8 T cells. The memory CD8 T cells from ASYMP individuals expressed unique gene signatures characterized by higher levels of type I interferon (IFN), expansion and expansion/survival cytokines, and JAK/STAT pathways. Future studies on the genotype, phenotype, and function of antiviral CD8 T cells from "naturally protected" ASYMP individuals will help in the potential design of T-cell-based ocular herpes vaccines.
世界上很大一部分人口携带单纯疱疹病毒 1（HSV-1），这是传染性角膜盲的主要原因。HSV 特异性 CD8 T 细胞可预防疱疹病毒感染和疾病。然而，与无症状（ASYMP）个体相关的 CD8 T 细胞的基因组、表型和功能特征，这些个体尽管被感染，但从未经历过任何复发性疱疹疾病，仍有待充分阐明。在这项研究中，我们使用高通量数字 NanoString nCounter 系统和流式细胞术比较了记忆 CD8 T 细胞表型、功能和表达水平的一个综合面板，这些细胞具有相同的 HSV-1 表位特异性，并且来自经过充分描述的受保护的 ASYMP 和非保护的有症状（SYMP）个体的新鲜分离外周血，这些个体有反复发作的疱疹病史。有趣的是，我们的结果表明，与 SYMP 个体中的更多单核中央记忆 CD62L CD44 CD8 T 细胞相比，来自 ASYMP 个体的记忆 CD8 T 细胞表达了一组独特的参与扩增和存活、I 型干扰素（IFN-I）和 JAK/STAT 途径的基因。与 SYMP 个体中的更多单核中央记忆 CD62L CD44 CD8 T 细胞相比，在 ASYMP 个体中检测到频繁的多功能 HSV 特异性效应记忆 CD62L CD44 CD8 T 细胞。揭示“自然保护”的 ASYMP 个体中抗病毒 CD8 T 细胞的基因型、表型和功能将有助于设计基于 T 细胞的眼部疱疹免疫治疗疫苗。世界上大量的人口携带单纯疱疹病毒 1（HSV-1），可能导致失明的复发性疱疹疾病。虽然大多数是无症状（ASYMP）个体，从未经历过任何复发性疱疹疾病，但有症状（SYMP）个体有反复发作的眼部疱疹病史。本研究阐明了与 ASYMP 个体中所见保护相关的记忆 CD8 T 细胞群体的表型、效应功能和基因特征。在 ASYMP 个体中检测到频繁的多功能 HSV 特异性效应记忆 CD8 T 细胞。相比之下，非保护的 SYMP 个体具有更多的中央记忆 CD8 T 细胞。来自 ASYMP 个体的记忆 CD8 T 细胞表达独特的基因特征，其特征是更高水平的 I 型干扰素（IFN）、扩增和扩增/存活细胞因子以及 JAK/STAT 途径。对“自然保护”的 ASYMP 个体中抗病毒 CD8 T 细胞的基因型、表型和功能进行进一步研究，将有助于设计基于 T 细胞的眼部疱疹疫苗。
