NIH PATHWAY TO INDEPENDENCE APPLICATION (K99/R00)

描述（由申请人提供）：新生儿特别容易感染传染病。该建议的目标是将不同的发展阶段与CD8+ TCR的多样性和免疫防御联系起来。为了实现这一目标，我们将研究抗原特异性新生儿和成人CD8+ T细胞对急性和持续性感染产生适当免疫反应的能力。我们的总体重点是通过检查新生儿CD8+ T细胞克隆型在发育过程中维持到何种程度，并在成年后提供免疫防御，来确定新生儿急性和持续性感染的长期后果。我们的中心假设是，生命早期的感染“锁定”了一种较少多样性和结构独特的CD8+ TCR库，当成年后受到挑战时，这种库会阻碍免疫防御。我们预测，早期感染允许低亲和性的胎儿/新生儿CD8+ TCR克隆型主导成人记忆CD8+ T细胞区室，并将与T细胞免疫功能受损直接相关，以抵抗急性和慢性持续性感染。具体目标1 （SA1）在指导阶段完成，具体目标2 （SA2）在独立阶段执行。SA1：生命早期的急性感染是否“锁定”了较少多样性的记忆CD8+ TCR库，从而损害了成人CD8+ T细胞免疫？这将通过用活感染载体免疫新生小鼠和成年小鼠，然后用HSV-1挑战所有小鼠来检验。SA2：生命早期的持续感染是否会改变组织常驻记忆细胞的克隆组成及其在生命后期控制潜伏期的能力？我们将评估HSV-1将新生儿库隔离到三叉神经节的能力，并将库多样性与潜伏感染期间的免疫监测和功能联系起来。从这些研究中获得的知识将更好地告诉我们生命早期感染如何改变成人记忆T细胞库的克隆组成，并为在早期发育的关键阶段改善长期T细胞免疫提供见解。

DESCRIPTION (provided by applicant): 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. Many acute and persistent viral infections are transmitted early in life and are responsible for long-term morbidity and mortality. At the conclusion of these studies, we expect to have a better mechanistic understanding of these immune impairments, while also offering insight into safe and effective strategies to boost immunity during critical stages of early development.