Specificity and Function of CMV-specific CD8+ T Cells

描述(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的协同表达可以下调感染细胞中I类MHC的表达，有效地阻断新合成的CMV抗原在体外向CD8细胞毒性T细胞(CTL)递送。然而，CD8CTL在体内是控制CMV持续感染的关键效应细胞，这被认为反映了感染细胞在I类MHC下调之前对少数免疫优势病毒抗原的特异性CD8CTL的贡献。申请人最近使用一种删除了美国基因的CMV毒株进行的研究表明，体内CMV特异性CTL谱系比以前所认识的要大得多，也更加多样化。这一发现表明，在巨细胞病毒免疫治疗或疫苗接种的发展中加入更多的巨细胞病毒抗原可能是重要的。这些实验旨在鉴定CD8CTL识别的新的CMV抗原，以深入了解它们在正常个体中控制CMV复制的作用，并确定单个US蛋白和细胞反规避策略对抑制向CTL递呈抗原的影响。 其具体目的是：1.鉴定编码CD8CMV特异性细胞毒性T细胞识别新抗原的巨细胞病毒基因。2.检测具有保护性免疫的健康CMV个体特异性CD8T细胞的频率和功能。3.探讨不同病毒免疫逃避蛋白和细胞反逃避策略对CMV感染细胞向CD8CTL递呈CMV抗原的影响。

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.