Evolution of T cell immunity in blood and tissues over childhood

项目总结 婴儿期和儿童期的免疫系统发育为终生保护性免疫奠定了基础。 众所周知，婴儿和儿童更容易感染无处不在的呼吸道和粘膜病原体 哪些成年人以前接触过。然而，我们最近在新冠肺炎大流行中的经验， 儿童明显比成年人更不容易感染这种新型呼吸道病毒 SARS-CoV-2，表明儿童的免疫系统对新遇到的情况可以高度有效 病原体。幼稚T细胞的多样性，它们分化为组织归巢效应细胞的能力， 它介导了感染部位的病原体清除，以及随后产生的长寿记忆T 细胞是免疫反应中的关键事件，在儿童中没有定义。通过以下方式确定机制 哪些T细胞对抗原挑战做出反应，并在整个婴儿期和 儿童对于改进疫苗和免疫疗法以保护下一代至关重要。我的 实验室一直在研究小鼠模型和包括组织在内的新型人类样本的早期生命免疫 来自婴儿和儿童器官捐赠者，重点是如何保护组织驻留的记忆T细胞(TRM) 在幼年时期就成熟了，在童年时期就成熟了。我们开创了人类组织免疫研究的先河 在器官捐赠者组织中，识别跨越体内组织的大多数T细胞是TRM，它始于 在肠道中形成早期生命并随着年龄的增长而成熟。我们已经确定了根本和内在的区别 比较了婴幼儿与成人T细胞最早阶段的T细胞活化情况，并研究了抗病毒作用 不同儿科人群对SARS-CoV-2免疫状况的研究我们的中心假设是儿科T细胞反应 由于内在信号机制、特定的组织环境和抗原暴露，它们是不同的 历史。在这项研究中，我们将以我们的结果、人体样本和队列为基础来阐明 儿童T细胞的不同反应及其在组织中的分化命运、成熟和进化反应 到疫苗。在目标1中，我们将确定儿童幼稚T细胞的不同激活机制，包括 T细胞结合形成和细胞分裂过程中的早期事件如何影响早期生命和儿童的细胞命运 小鼠和人类的T细胞。在目标2中，我们将阐明TRM分化途径和 人肠道和肺TRM的高维单细胞图谱研究 所有年龄段的儿童，并使用小鼠模型来解决持久性和组织环境在 TRM成熟。在目标3中，我们将分析儿童时期的疫苗特异性免疫反应和进化 建立了以前有不同临床表现的SARS-CoV-2感染的儿童队列，或 都没有被感染。我们将评估病毒特异性T细胞和抗体对当前COVID mRNA的反应 疫苗随时间和年龄的变化。总之，拟议的研究将全面定义免疫系统 在童年这个关键的和形成的窗口中成熟。

PROJECT SUMMARY Immune system development during infancy and childhood sets the stage for a lifetime of protective immunity. Infants and children are known to be more susceptible to ubiquitous respiratory and mucosal pathogens for which adults have prior exposures. However, our recent experience in the COVID-19 pandemic, in which children were markedly less susceptible than adults to disease from infection with the novel respiratory virus SARS-CoV-2, indicate that children's immune systems can be highly effective to newly encountered pathogens. The diverse repertoire of naïve T cells, their ability to differentiate to tissue homing effector cells, which mediate pathogen clearance at infection sites, and the subsequent generation of long-lived memory T cells are critical events in immune responses that are not defined in children. Identifying the mechanisms by which T cells respond to antigenic challenges and establish immunological memory throughout infancy and childhood are essential for improving vaccines and immunotherapies to protect the next generation. My laboratory has been studying early life immunity in mouse models and novel human samples, including tissues from infant and pediatric organ donors, with a focus on how protective tissue resident memory T cells (TRM) become established in early life and mature over childhood. We pioneered the study of human tissue immunity in organ donor tissues, identifying that the majority of T cells across tissues in the body are TRM, which begin to form in early life in intestines and mature over age. We have identified fundamental and intrinsic differences in infant compared to adult T cells at the earliest stages in T cell activation and have investigated anti-viral immunity to SARS-CoV-2 in different pediatric cohorts. Our central hypothesis is that pediatric T cell responses are distinct due to intrinsic signaling mechanisms, the specific tissue environment, and the antigenic exposure history. In this study, we will build on our results, human samples, and cohorts to elucidate mechanisms for the distinct responses of pediatric T cells and their differentiation fate, maturation in tissues, and evolving response to vaccines. In aim 1, we will identify mechanisms for the distinct activation of pediatric naïve T cells, including how early events during T cell conjugate formation and cell division impact cell fate in early life and childhood for mouse and human T cells. In aim 2, we will elucidate TRM differentiation pathways and the role of the tissue in TRM maturation by high dimensional single cell profiling of human TRM in intestines and lungs across all ages of childhood, and use mouse models to address the role of persistence and tissue environment in TRM maturation. In aim 3, we will analyze vaccine-specific immune responses and evolution over childhood in established cohorts of children who previously had different clinical manifestations of SARS-CoV-2 infection, or were not infected. We will assess virus-specific T cell and antibody responses to the current COVID mRNA vaccines over time and age. Together, the proposed studies will comprehensively define immune system maturation over this critical and formative window of childhood.