Evolution of T cell immunity in blood and tissues over childhood

项目摘要 婴儿期和儿童期的免疫系统发育为一生的保护性免疫奠定了基础。 已知婴儿和儿童更容易受到无处不在的呼吸道和粘膜病原体的影响， 哪些成年人曾接触过然而，我们最近在COVID-19疫情中的经验， 儿童对新型呼吸道病毒感染疾病的易感性明显低于成人 SARS-CoV-2表明，儿童的免疫系统可以非常有效地应对新遇到的 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， 介导感染部位的病原体清除，以及随后产生的长寿命记忆T 细胞是免疫反应中的关键事件，在儿童中没有定义。确定机制， 其中T细胞对抗原攻击作出反应并在整个婴儿期建立免疫记忆， 儿童期的疫苗接种对于改进疫苗和免疫疗法以保护下一代至关重要。我 一个实验室一直在研究小鼠模型和新的人类样本（包括组织）的早期生命免疫力 从婴儿和儿科器官捐赠者，重点是如何保护组织驻留记忆T细胞（TRM） 在幼年时就已形成，并在童年时成熟。我们开创了人体组织免疫的研究 在器官供体组织中，鉴定出体内组织中的大多数T细胞是TRM，其开始 在生命早期在肠道中形成并随着年龄的增长而成熟。我们已经确定了根本性和内在的差异 在婴儿中与成人T细胞相比，在T细胞活化的最早阶段， 免疫SARS-CoV-2在不同的儿科队列。我们的中心假设是儿童T细胞反应 由于内在信号传导机制、特定的组织环境和抗原暴露， 历史在这项研究中，我们将建立在我们的结果，人类样本和队列，以阐明机制， 儿科T细胞的不同反应及其分化命运，组织中的成熟和演变反应 到疫苗。在目标1中，我们将确定儿科幼稚T细胞的独特激活机制，包括 T细胞结合物形成和细胞分裂期间的早期事件如何影响早期生命和儿童期的细胞命运 for mouse小鼠and human人T cells细胞.在目标2中，我们将阐明TRM分化途径和TRM的作用。 通过对肠和肺中人TRM的高维单细胞谱分析， 所有年龄的儿童，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，我们将分析疫苗特异性免疫应答和儿童期的演变， 已建立的曾有不同SARS-CoV-2感染临床表现的儿童队列，或 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， 随着时间和年龄的增长，总之，拟议的研究将全面定义免疫系统 在这个关键的和形成性的童年窗口中成熟。

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.