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Upregulation of Multiple CD8+ T Cell Exhaustion Pathways Is Associated with Recurrent Ocular Herpes Simplex Virus Type 1 Infection
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-15 , DOI: 10.4049/jimmunol.2000131
Pierre-Grégoire Coulon 1 , Soumyabrata Roy 1 , Swayam Prakash 1 , Ruchi Srivastava 1 , Nisha Dhanushkodi 1 , Stephanie Salazar 1 , Cassandra Amezquita 1 , Lan Nguyen 1 , Hawa Vahed 1 , Angela M Nguyen 1 , Wasay R Warsi 1 , Caitlin Ye 1 , Edgar A Carlos-Cruz 1 , Uyen T Mai 1 , Lbachir BenMohamed 2, 3, 4
Affiliation  

Key Points HSV-specific CD8+ T cells from HSV-1–infected symptomatic patients are exhausted. Blocking of LAG-3 and PD-1 synergistically restored anti-HSV CD8+ T cell responses. LAG-3 and PD-1 blockade reduced recurrent ocular herpes in HSV-1–infected mice. Visual Abstract 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-A*0201–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-A*0201 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.

中文翻译:

多种 CD8+ T 细胞耗竭途径的上调与复发性眼部单纯疱疹病毒 1 型感染有关

要点 来自 HSV-1 感染的有症状患者的 HSV 特异性 CD8+ T 细胞已耗尽。阻断 LAG-3 和 PD-1 可协同恢复抗 HSV CD8+ T 细胞反应。LAG-3 和 PD-1 阻断减少了 HSV-1 感染小鼠的复发性眼疱疹。视觉摘要 世界上很大一部分人口携带潜伏的 HSV 1 型 (HSV-1)。抗病毒 CD8+ T 细胞和 HSV-1 之间的串扰似乎控制了潜伏期/再激活周期。我们发现,与健康的无症状个体相比,在有症状 (SYMP) 患者中,具有相同 HLA-A*0201 限制性 HSV-1 表位特异性的 CD8+ T 细胞表达与主要 T 细胞耗竭途径相关的多个基因和蛋白质,并且功能失调. 用抗 LAG-3 和抗 PD-1 拮抗剂 mAb 阻断免疫检查点可协同恢复 1) 在 SYMP 个体和 SYMP HLA-A*0201 转基因小鼠中的体外抗病毒 CD8+ T 细胞的频率和功能;2) 在 HSV-1 感染的 SYMP HLA-A*0201 转基因小鼠体内。这与病毒再激活和复发性眼疱疹疾病的显着减少有关。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疱疹铺平了道路。
更新日期:2020-06-15
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