T cell response to fibroblast-trophic CMV vaccine in humans

描述（由申请方提供）：本项目的目的是确定接种成纤维细胞适应性CMV疫苗的人是否会产生Louis Picker小组最近在接种成纤维细胞适应性恒河猴-CMV疫苗的猴中报告的异常非常规CD 8 + T细胞应答。这些反应涵盖了非常广泛的肽，是混杂的MHC亚型，和许多的CD 8 + T细胞识别的MHC II类分子的背景下的肽。在猴或人中，非常规T细胞不是由天然CMV感染引起的，并且汉森等人表明它们仅由成纤维细胞适应的CMV引起，即缺乏形成进入巨噬细胞、内皮和上皮细胞所需的糖蛋白的五聚体复合物的能力的CMV。猴子和人类的免疫系统在几个方面不同，最显着的是它们的MHC基因，在恒河猴中是非常多基因和多态的。目前尚不清楚人类成纤维细胞适应的CMV疫苗是否会在人类中引起类似的非常规反应。为了解决这个问题，我们将利用正在进行的基于Towne和Toledo株的成纤维细胞适应CMV疫苗的临床研究。将在接种前和接种后定期采集PBMC。将对血清转化的受试者进行白细胞分离术，以建立PBMC储存库，并能够对应答进行深入分析。将分析T细胞应答以确定CD 8 + T细胞应答的特异性、肽识别的广度和MHC限制的性质。

DESCRIPTION (provided by applicant): The objective of this project is to determine whether humans vaccinated with a fibroblast-adapted CMV vaccine develop the extraordinary unconventional CD8+ T cell responses that were recently reported by Louis Picker's group in monkeys vaccinated with a fibroblast-adapted rhesus-CMV. These responses covered an extremely broad range of peptides, were promiscuous with respect to MHC isoforms, and many of the CD8+ T cells recognized peptides in the context of MHC class II molecules. Unconventional T cells are not elicited by natural CMV infection in either monkeys or humans, and Hansen et al showed that they were only elicited by fibroblast-adapted CMV, i.e. CMV that lacks the ability to form a pentameric complex of glycoproteins needed for entry into macrophages, endothelial and epithelial cells. Monkey and human immune systems differ in several ways, most dramatically in their MHC genes, which in rhesus macaques are extremely polygenic and polymorphic. It is unknown whether a human fibroblast-adapted CMV vaccine would elicit similarly unconventional responses in humans. To address this question, we will exploit an ongoing clinical study of fibroblast-adapted CMV vaccines based on the Towne and Toledo strains in humans. PBMC will be collected before and at regular intervals after vaccination. Leukopheresis will be performed on subjects who seroconvert to establish a repository of PBMC and enable intensive dissection of the response. T cell responses will be analyzed to determine the specificity of the CD8+ T cell response, the breadth of peptide recognition, and the nature of MHC restriction.