Specificity and Function of CMV-specific CD8+ T Cells

描述（由申请方提供）：巨细胞病毒（CMV）与其他疱疹病毒一样，已进化出逃避免疫识别的机制，从而延长急性感染并建立潜伏期。在病毒基因组的US区域中编码的四种病毒蛋白的协调表达起到下调感染细胞中的I类MHC的作用，有效地阻断新合成的CMV抗原在体外呈递给CD8 +细胞毒性T细胞（CTL）。然而，CD8 + CTL是控制体内持续CMV感染的关键效应细胞，这被认为反映了在I类MHC下调之前由感染细胞呈递的对少数免疫显性病毒抗原特异的CD8 + CTL的贡献。本申请人最近使用缺失US基因并且可以展示来自病毒蛋白质组的所有潜在免疫原性表位的CMV毒株进行的研究已经证明，体内CMV特异性CTL库比以前认识到的大得多并且更多样化。研究结果表明，额外的CMV抗原可能是重要的，包括在发展免疫疗法或疫苗接种CMV。拟议的实验旨在确定新的CMV抗原CD8 + CTL识别，以提供他们的作用，在控制正常个体的CMV复制的见解，并确定个别美国蛋白质和细胞的反侵入策略对抑制抗原呈递给CTL的影响。 具体目标是：1.鉴定编码CD8 + CMV特异性细胞毒性T细胞识别的新型抗原的巨细胞病毒基因。2.确定具有保护性免疫的健康CMV +个体中对单个CMV抗原特异性的CD8 + T细胞的频率和功能。3.确定单个病毒免疫逃避蛋白和细胞反逃避策略对CMV感染细胞将CMV抗原呈递给CD8 + 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.