Specificity and Function of CMV-specific CD8+ T Cells

描述（由申请人提供）：巨细胞病毒（CMV），像其他疱疹病毒一样，已经进化出逃避免疫识别的机制，使其能够延长急性感染并建立潜伏期。病毒基因组US区编码的四种病毒蛋白协同表达可下调感染细胞中的I类MHC，在体外有效阻断新合成的CMV抗原向CD8 +细胞毒性T细胞（CTL）的呈递。然而，CD8 + CTL是体内控制持续性巨细胞病毒感染的关键效应细胞，这被认为反映了CD8 + CTL对感染细胞在I类MHC下调之前呈现的一些免疫显性病毒抗原的贡献。申请人最近使用删除US基因的巨细胞病毒株进行的研究表明，体内巨细胞病毒特异性CTL库比以前认为的要大得多，也更多样化。该毒株可以显示来自病毒蛋白质组的所有潜在免疫原性表位。研究结果表明，在CMV免疫治疗或疫苗接种的发展中，额外的CMV抗原可能是重要的。本实验旨在鉴定CD8 + CTL识别的新型CMV抗原，以深入了解其在正常个体中控制CMV复制的作用，并确定单个US蛋白和细胞反逃避策略对抑制抗原呈递CTL的影响。

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV), like other herpes viruses, has evolved mechanisms to evade immune recognition that allow it to prolong acute infection and to establish latency. The coordinated expression of four viral proteins encoded in the US region of the viral genome functions to downregulate class I MHC in infected cells, effectively blocking the presentation of newly synthesized CMV antigens to CD8 + cytotoxic T cells (CTL) in vitro. However, CD8 + CTL are critical effector cells for controlling persistent CMV infection in vivo and this was thought to reflect the contributions of CD8 + CTL specific for a few immunodominant viral antigens that were presented by infected cells prior to the downregulation of Class I MHC. Recent studies by the applicant using a strain of CMV that is deleted of the US genes and can display all potentially immunogenic epitopes from the viral proteome have demonstrated that the CMV-specific CTL repertoire in vivo is much larger and more diverse than previously appreciated. The findings suggest that additional CMV antigens may be important to include in the development of immunotherapy or vaccination for CMV. The proposed experiments are designed to identify novel CMV antigens recognized by CD8 + CTL, to provide insights into their role in controlling CMV replication in normal individuals, and to determine the effects of individual US proteins and cellular counterevasion strategies on the inhibition of antigen presentation to CTL. The specific aims are: 1. To identify cytomegalovirus genes encoding novel antigens recognized by CD8 + CMV-specific cytotoxic T cells. 2. To determine the frequency and function of CD8 + T cells specific for individual CMV antigens in healthy CMV + individuals with protective immunity. 3. To determine the effects of individual viral immune evasion proteins and cellular counter evasion strategies on the presentation of CMV antigens to CD8 + CTL by CMV-infected cells.