Immune Memory

我们的目标是了解一种成功的疫苗如何诱导长期的免疫记忆和保护 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 关于黄热病病毒(YFV-17D)疫苗诱导的人类免疫反应。这是我们最大的 有效的疫苗，并诱导持续数十年的长期免疫。另外，由于YFV-17D是一种活的 减毒疫苗和大多数美国人都不会接触YFV-，这提供了一种独特的 有机会分析人类在初次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。其中一个 了解一种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，可以用来开发 针对新出现的疾病的新疫苗。在上一个资金周期中，我们取得了很大的进展 人类记忆T和B细胞对YFV和YFV免疫应答的研究进展 接种天花和流感疫苗。在本次续费申请中，我们将重点研究 CDS T细胞，并研究调节人类效应和记忆CDS T细胞的机制 差异化。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 调节幼稚的因素对CDS T//分化的影响。2)分析人体在体内的周转 检测YFV特异性CDS T细胞的归巢潜能。3)定义基因组和表观遗传学 人类记忆CDS T细胞分化过程中发生的变化。这些研究将提供第一个 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，能够识别、分离和鉴定分化的细胞亚群。 T细胞应答过程中表观DNA甲基化标记的检测 至于CD8T细胞对急性和慢性病毒感染的反应将提供潜在的 记忆CDS T细胞分化如何被全局调控的机械论观点。

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.