Role of CD8+ T Cells in TMEV Resistance and Susceptibili

描述(由申请人提供) 脑内接种泰勒氏小鼠脑脊髓炎病毒(TMEV)导致慢性 炎性脱髓鞘导致易感小鼠的临床症状。鉴于潜在的病毒病因和慢性脱髓鞘进展的相似性，该TMEV系统被认为是研究人类多发性硬化症(MS)的最佳动物模型之一。已有大量研究报道了针对TMEV的II类限制性的CD4+T细胞反应，它似乎在病毒的致病机制中发挥了重要作用。利用缺乏细胞毒性T细胞功能的X32-微球蛋白和穿孔素缺陷小鼠，我们证明了细胞毒性功能对于C57BL/6背景的耐药小鼠预防这种病毒诱导的脱髓鞘疾病是重要的。然而，对于针对TMEV的I类限制性CD8+T细胞反应，特别是在敏感株中，人们知之甚少，尽管这种类型的反应被认为是保护宿主免受病毒感染的最有效的类型。在过去的资助期间，我们已经为耐药的C57BL/6小鼠确定了一个主要和两个次要的H-2DB限制性CTL表位，并类似地为敏感的SJL/J小鼠确定了一个主要和两个次要的H-2ks限制性CTL表位。 TMEV衣壳蛋白全长的重叠肽。由于对TMEV诱导的脱髓鞘的抵抗与H2D基因座有关，而敏感小鼠缺乏病毒特异性的H-2D限制性细胞毒性T细胞，我们推测病毒特异性CD8+细胞毒性T细胞的效率和/或频率可能取决于耐药小鼠和敏感小鼠在I类限制方面的差异。作为人类多发性硬化症的模型，我们建议研究这些针对主要和次要病毒表位的细胞毒性T细胞在对泰勒氏病毒诱导的脱髓鞘疾病的抗性和/或易感性中的作用和命运。这项研究的具体目的包括：1)评估病毒表位特异性CD8+T细胞在耐药和易感小鼠脱髓鞘疾病过程中的水平和去向；2)确定病毒特异性CD8+T细胞在TMEV诱导的脱髓鞘疾病保护和/或发病机制中的作用；3)检测H-2D和H-2K-限制对TMEV特异性CTL在耐药性/敏感性中的意义及其这种倾斜限制的可能机制。我们相信，我们建议的研究将为S抗病毒诱导的潜在控制机制提供重要信息。 免疫介导的脱髓鞘是研究人类多发性硬化的相关动物模型。

Description (provided by applicant) ntracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical symptoms in susceptible mice. In light of the potential viral etiology and similarities in the progression of chronic demyelination, this TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS). Extensive studies on the class II-restricted, CD4+ T cell response specific for TMEV, which appears to play an important role in viral pathogenesis, have been reported. Using X32-microglobulin and perforin deficient mice lacking cytotoxic T cell function, we have demonstrated that cytotoxic function is important for protection from this virus-induced demyelinating disease in resistant mice with the C57BL/6 background. However, very little is known about the class I-restricted, CD8+ T cell response against TMEV particularly in susceptible strains, although this type of response is known to be the most efficient in protecting the host from viral infections. During the past grant period, we have identified one major and two minor H-2Db-restricted CTL epitopes for resistant C57BL/6 mice, and similarly one predominant and two subdominant H-2Ks-restricted CTL epitopes for susceptible SJL/J mice using overlapping peptides of the entire capsid proteins of TMEV. Because resistance to TMEV-induced demyelination is associated with the H2D locus and susceptible mice lack virus-specific, H-2Drestricted cytotoxic T cells, we speculate that the efficiency and/or frequency of virus-specific CD8+ cytotoxic T cells may be dependent on the differences in the class I restriction between resistant and susceptible mice. We propose here to examine the role and fate of these cytotoxic T cells specific for the predominant and subdominant viral epitopes in resistance and/or susceptibility to Theiler's virusinduced demyelinating disease as a model for human multiple sclerosis. The specific aims for the proposed studies include: 1) To assess the level and fate of CD8+ T cells specific for viral epitopes in resistant and susceptible mice during the course of demyelinating disease; 2) To determine the role of virus-specific CD8+ T cells in protection from and/or pathogenesis of TMEV-induced demyelinating disease; 3) To examine the significance of H-2D vs H-2K-restriction for TMEV-specific CTL in resistance/susceptibility and the potential mechanism of this skewed restriction. We believe that our proposed studies will yield important information on the potential control mechanism(s) against virusinduced, immune-mediated demyelination, which is a relevant animal model for studying human MS.