Chentoufi Aziz A, Khan Arif A, Srivastava Ruchi, Karan Sweta, Lekbach Yassir, Vahed Hawa, BenMohamed Lbachir
Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
Viruses. 2025 Apr 24;17(5):606. doi: 10.3390/v17050606.
Herpes simplex virus (HSV)-specific CD8 T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8 T cells that play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) patients (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent ocular herpes disease) had more undifferentiated and dysfunctional HSV-specific CD8 T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8 T cells. Here, we report that HSV-specific CD8 T cells from 10 SYMP patients, but not HSV-specific CD8 T cells from 10 ASYMP patients, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57) and exhausted (PD-1) CD8 T cells; (ii) late terminally differentiated (KLRG1), non-proliferating CD8 T cells; (iii) HSV-specific CD8 T cells which decreased in number over time and were not homeostatically maintained, as indicated by a reduction in the number of CD127CD8 T cells; (iv) loss of the co-stimulatory molecule CD28 on HSV-specific CD8 T cells; and (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8 T cells. Our findings provide insights into the role of senescence in HSV-specific CD8 T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.
单纯疱疹病毒（HSV）特异性CD8 T细胞可保护小鼠免受疱疹感染和疾病侵害。然而，在HSV-1血清阳性的健康无症状（ASYMP）患者（从未患过临床疱疹疾病）中发挥“天然”保护关键作用的HSV特异性CD8 T细胞的表型和功能仍有待确定。我们之前报道过，有症状（SYMP）患者（频繁发作复发性眼部疱疹疾病）拥有更多未分化且功能失调的HSV特异性CD8 T细胞。相比之下，健康的ASYMP个体维持着显著更高比例的分化多功能CD8 T细胞。在此，我们报告，来自10名SYMP患者的HSV特异性CD8 T细胞具有细胞衰老的表型和功能特征，而来自10名ASYMP患者的HSV特异性CD8 T细胞则没有，这些特征包括：（i）衰老（CD57）和耗竭（PD-1）CD8 T细胞的高频率；（ii）晚期终末分化（KLRG1）、不增殖的CD8 T细胞；（iii）随着时间推移数量减少且未通过稳态维持的HSV特异性CD8 T细胞，这表现为CD127⁺CD8 T细胞数量减少；（iv）HSV特异性CD8 T细胞上共刺激分子CD28的丧失；以及（v）HSV特异性CD8 T细胞效应分子（颗粒酶B和穿孔素）产生减少。我们的研究结果为衰老在HSV特异性CD8 T细胞对复发性疱疹易感性中的作用提供了见解，并对针对人类复发性疱疹的基于T细胞的免疫治疗策略具有启示意义。
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