T cell response to fibroblast-trophic CMV vaccine in humans

描述(申请人提供)：该项目的目标是确定接种成纤维细胞适应的CMV疫苗的人是否会在接种成纤维细胞适应的恒河猴CMV疫苗的猴子中产生Louis Picker团队最近报告的非凡的非常规CD8+T细胞反应。这些反应覆盖了非常广泛的多肽，与MHC亚型混杂，许多CD8+T细胞在MHC II类分子的背景下识别多肽。无论是在猴子还是在人类身上，非常规T细胞都不会被CMV自然感染所诱导，Hansen等人发现它们只由成纤维细胞适应的CMV诱导，即CMV缺乏形成进入巨噬细胞、内皮细胞和上皮细胞所需的糖蛋白五聚体复合体的能力。猴子和人类的免疫系统在几个方面不同，最显著的是它们的MHC基因，恒河猴的MHC基因是非常多基因和多态的。目前尚不清楚人成纤维细胞适应的巨细胞病毒疫苗是否会在人类身上引起类似的非常规反应。为了解决这个问题，我们将开展一项正在进行的基于人类Towne和Toledo株的成纤维细胞适应的CMV疫苗的临床研究。在接种疫苗前和接种后定期采集PBMC。将对血清转换的受试者进行白细胞分离，以建立PBMC存储库，并对应答进行密集解剖。将分析T细胞反应，以确定CD8+T细胞反应的特异性，肽识别的广度，以及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.