Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). However, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS can stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique. Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus and influenza A virus) proteins, and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a positive, suggesting a cytotoxic phenotype, and stuck to EBV-infected cells. Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV contribute to inflammation causing CNS injury.IMPORTANCE EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage. To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

中文翻译：

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爱泼斯坦-巴尔病毒特异的CD8 T细胞在多发性硬化症中选择性渗入大脑，并与病毒感染的细胞局部相互作用：病毒驱动的免疫病理机制的线索。

爱泼斯坦-巴尔病毒（EBV）是一种普遍存在的疱疹病毒，与多发性硬化症（MS）（中枢神经系统的慢性炎症性疾病）密切相关。但是，将EBV感染与MS病理联系起来的机制尚不确定。神经病理学和免疫学研究表明，CNS中持续的EBV感染可以刺激旨在清除病毒但无意中引起CNS损伤的CD8 T细胞反应。由于EBV特异性CD8 T细胞的原位演示及其效应功能缺失，我们使用五聚体技术在MS脑组织中搜索EBV特异性CD8 T细胞。分析了来自12名进行性MS和已知HLA I类基因型供体的死后脑样本。用HLA匹配的五聚体和EBV编码蛋白的免疫原性肽对脑切片进行染色，控制病毒（巨细胞病毒和甲型流感病毒）蛋白和髓磷脂碱性蛋白。在11/12 MS供体的白质损伤和/或脑膜中可以看到识别EBV生命周期潜伏期和裂解期表达蛋白的CD8 T细胞。识别单个EBV表位的CD8 T细胞的分数（中值）为CNS浸润CD8 T细胞的0.5％至2.5％。在来自4/12 MS供体的大脑切片中以较低的频率（≤0.3％）检测到巨细胞病毒特异性CD8 T细胞。CNS浸润的EBV特异性CD8 T细胞为CD107a阳性，表明具有细胞毒性表型，并粘附在EBV感染的细胞上。与局部EBV失调一起，MS脑中EBV特异性CD8 T细胞的选择性富集支持了以下观点：偏向EBV的免疫反应偏向炎症，导致CNS损伤。重要事项EBV可在大多数个体中建立终生无症状感染，并且很少引起感染性单核细胞增多症和恶性肿瘤，如淋巴瘤。该病毒还与病因未知的慢性神经炎性疾病MS密切相关。传染性单核细胞增多症增加了罹患MS的风险，MS患者对EBV的免疫反应性更高，表明对病毒的控制不充分。先前的研究表明，CNS中持续的EBV感染会刺激免疫病理反应，从而导致旁观者神经细胞受损。为了验证这一点，我们需要确定造成CNS有害抗病毒应答的免疫元凶。在这个研究中，我们分析了MS捐献者的死后大脑，结果表明识别EBV的CD8细胞毒性T细胞进入大脑，并与受病毒感染的细胞发生局部相互作用。这种抗病毒CD8 T细胞介导的免疫应答可能有助于MS病理。