Neonatal Infections and Memory T c ell Repertoire R00

项目摘要/摘要： 新生儿特别容易感染传染病。这项提议的目标是将不同的 随着CD8+TCR谱系的多样化和免疫防御的发展阶段。要完成 为了达到这个目标，我们将研究抗原特异的新生儿和成人CD8+T细胞产生 针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 通过检查新生儿感染的程度来评估新生儿急性持续感染的长期后果 CD8+T细胞克隆类型在发育过程中保持不变，并在成年后提供免疫防御。我们的 中心假说是生命早期的感染锁定了一个种类较少且结构不同的CD8+TCR 当成年后受到挑战时，阻碍免疫防御的曲目。我们预测早期感染会导致 低亲和力胎儿/新生儿CD8+TCR克隆型主导成人记忆CD8+T细胞隔间和意志 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。 这将按如下方式进行测试，具体目标1(SA1)将在指导阶段和具体阶段完成 目标2(SA2)在独立阶段进行。SA1：生命早期的急性感染是否不那么多样化 会损害成人CD8+T细胞免疫的记忆CD8+TCR谱系？将通过免疫来检查这一点 新生小鼠和成年小鼠使用活的感染媒介，后来用HSV-1攻击所有小鼠。SA2：DO 生命早期的持续感染改变了组织驻留记忆细胞的克隆组成和它们的能力 在以后的生活中控制延迟？我们将评估HSV-1将新生儿谱系隔离到 三叉神经节及其与潜伏期免疫监视和功能相关的谱系多样性 感染。从这些研究中获得的知识将更好地告诉我们生命早期的感染是如何改变 成人记忆T细胞池的克隆组成并为改善长效T细胞提供洞察力 在早期发育的关键阶段的免疫力。

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.