Immune Memory

我们的目标是了解一种成功的疫苗是如何诱导长期免疫记忆和保护性免疫反应的。 人类的免疫力。为了实现这一目标，我们已经开始了详细的细胞和分子表征 黄热病病毒（YFV-17 D）疫苗诱导的人体免疫应答。这是我们历史上 有效的疫苗，并诱导持续数十年的长期免疫。此外，由于YFV-17 D是一种活的 减毒疫苗和大多数美国人口没有暴露于YFV-，这提供了一个独特的 有机会分析人类在原发性感染过程中的抗病毒反应，然后 监测感染消退后免疫记忆的产生和维持。之一 了解成功的疫苗如何诱导长期保护性免疫的潜在好处是， 这些知识可以用于改进其他效果较差的疫苗，更重要的是， 新疫苗对抗新出现的疾病。在上一轮融资中，我们已经取得了重大进展。 在表征人类记忆T和B细胞不仅对YFV而且对 接种天花和流感疫苗。在这次更新申请中，我们将重点研究 CDS-T细胞和研究调节人类效应和记忆CDS-T细胞的机制 分化为了实现我们的目标，我们提出了以下具体目标：1）识别转录 调节幼稚细胞向效应细胞CDS T细胞分化的因子。2)为了分析人的体内周转， YFV特异性CDS T细胞并检查其归巢潜力。3)为了定义基因组和表观遗传 人类记忆CDS T细胞分化过程中发生的变化。这些研究将首次提供 在人类CDS T细胞分化后发生的转录变化的观点，并将提供 独特的标记物，其将能够鉴定、分离和表征分化的细胞亚群。 在T细胞应答进展过程中检查表观遗传DMA甲基化标记，以及 如CD 8 T细胞对急性与慢性病毒感染的反应之间， 记忆CDS T细胞分化如何在全球范围内受到调节的机制观点。

Our goal is to understand how a successful vaccine induces long-term immunological memory and protective immunity in humans. To achieve this goal we have initiated a detailed cellular and molecular characterization of human immune responses induced by the yellow fever virus (YFV-17D) vaccine. This is one of our most efficacious vaccines and induces long-term immunity that lasts for decades. Also, since YFV-17D is a live attenuated vaccine and most of the U.S. population is not exposed to YFV-, this provides a unique opportunity to analyze antiviral responses in humans during the course of a primary infection and then to monitor the generation and maintenance of immune memory after resolution of the infection. One of the potential benefits of understanding how a successful vaccine induces long-term protective immunity is that this knowledge can be applied to improving other less effective vaccines and, more importantly, to develop new vaccines against emerging diseases. During the previous cycle of funding we have made substantial progress in characterizing human memory T and B cell responses not only to YFV but also after immunization with small pox and influenza vaccines. In this renewal application we will focus our studies on CDS T cells and examine the mechanisms that regulate human effector and memory CDS T cell differentiation. The following specific aims are proposed to achieve our goals: 1) To identify transcription factors that regulate naive to effector CDS Tee// differentiation. 2) To analyze the in vivo turnover of human YFV specific CDS T cells and to examine their homing potential. 3) To define the genomic and epigenetic changes that occur during human memory CDS T cell differentiation.These studies will will provide the first view of the transcriptional changes that occur following CDS T cell differentiation in humans and will provide unique markers that will enable identification, isolation, and characterization of the differentiated cell subsets. Examination of the epigenetic DMA methylation marks during the progression of the T cell response, as well as between CD8 T cells responding to acute versus chronic viral infections will provide a potential mechanistic view of how memory CDS T cell differentiation is globally regulated.