Neonatal Infections and Memory T c ell Repertoire R00

项目概要/摘要： 新生儿特别容易感染传染病。该提案的目标是将各种 发展阶段与多样化的CD 8 + TCR库和免疫防御。完成 为了实现这一目标，我们将研究抗原特异性新生儿和成人CD 8 + T细胞产生 对急性和持续性感染的适当免疫反应。我们的总体重点是确定 通过检查新生儿急性和持续感染的程度， CD 8 + T细胞克隆型在整个发育过程中得以维持，并在成年时提供免疫防御。我们 中心假设是，生命早期的感染“锁定”了一种多样性较低且结构独特的CD 8 + TCR 在成年后受到挑战时阻碍免疫防御的所有功能。我们预测早期感染 低亲合力胎儿/新生儿CD 8 + TCR克隆型主导成人记忆CD 8 + T细胞区室， 与针对急性和慢性持续性感染的T细胞免疫功能受损直接相关。 这将按照以下方式进行测试，具体目标1（SA 1）将在辅导阶段完成，具体目标2（SA 1）将在辅导阶段完成。 目的2（SA 2）在独立期进行。SA 1：生命早期的急性感染是否“锁定”了较少的多样性 记忆性CD 8 + TCR库损害成人CD 8 + T细胞免疫？这将通过免疫来检查 用活的感染性载体感染新生和成年小鼠，随后用HSV-1攻击所有小鼠。SA 2：执行 生命早期的持续性感染改变了组织驻留记忆细胞的克隆组成， 在以后的生活中控制潜伏期？我们将评估HSV-1将新生儿的所有基因库隔离到 三叉神经节和相关库多样性与潜伏期免疫监视和功能 感染从这些研究中获得的知识将更好地告知我们生命早期的感染如何改变 克隆组成的成人记忆T细胞池，并提供洞察改善持久的T细胞 免疫力在早期发展的关键阶段。

Project Summary/Abstract: Neonates are particularly susceptible to infectious diseases. The goal of this proposal is to link various stages of development with diversification of the CD8+ TCR repertoire and immune defense. To accomplish this goal, we will investigate the capacity of antigen-specific neonatal and adult CD8+ T cells to generate appropriate immune responses against acute and persistent infections. Our overall focus is on determining the long-term consequences of acute and persistent infections in neonates by examining to what extent neonatal CD8+ T cell clonotypes are maintained through development and provide immune defense as adults. Our central hypothesis is that infections early in life 'lock-in' a less diverse and structurally distinct CD8+ TCR repertoire that hinders immune defense when challenged later as adults. We predict that early infections allow low avidity fetal/neonatal CD8+ TCR clonotypes to dominate adult memory CD8+ T-cell compartments and will directly correlate with impaired functionality of T cell immunity against acute and chronic persistent infections. This will be tested as follows, with specific aim 1 (SA1) being completed in the mentored phase and specific aim 2 (SA2) performed in the independent phase. SA1: Do acute infections early in life 'lock-in' a less diverse memory CD8+ TCR repertoire that impairs adult CD8+ T cell immunity? This will be examined by immunizing neonatal and adult mice with a live infectious vector and later challenging all mice with HSV-1. SA2: Do persistent infections early in life alter the clonal composition of tissue resident memory cells and their ability to control latency later in life? We will assess the ability of HSV-1 to sequester the neonatal repertoire into the trigeminal ganglia and correlate repertoire diversity with immune surveillance and functionality during latent infection. Knowledge gained from these studies will better inform us on how infections early in life alter the clonal composition of the adult memory T cell pool and provide insight into improving long-lasting T cell immunity during critical stages of early development.