Development of lung T cell responses in infant respiratory immunity

项目摘要 粘膜和屏障组织中的免疫反应对于保护个体免受无数 感染这些部位的病原体，并通过T细胞亚群在原位维持长期保护 淋巴细胞被称为组织驻留记忆T细胞(TRM)。在出生时，人类基本上是从一个不育的 在这种环境中，它们会迅速遇到多种不同的抗原，特别是在呼吸道和 消化系统。肺部和肠道也是婴儿易受感染的部位。 病原体，并可发展为危及生命的疾病。婴儿对传染病的这种脆弱性 以前被归因于他们的免疫系统不成熟；然而，婴儿的独特特性 免疫反应还没有完全确定，主要表现在循环或淋巴组织中。 而不是在关键的粘膜部位。确定婴儿介导抗病原体免疫的机制 反应，产生长期记忆，并保持动态平衡，对于设计新的策略是必不可少的 在最早的生命阶段进行疫苗接种和免疫调节。我们启动了对婴儿免疫力的研究 (由NIAID婴儿计划支持)四年前通过对人类T细胞分化的研究 来自器官捐赠者的婴儿组织样本，患有病毒感染的婴儿的呼吸道样本，以及小鼠的 流感病毒感染模型。总之，我们的发现揭示了早期生命免疫力的新方面 包括：1.婴儿记忆T细胞主要存在于肺和肠道中，而不存在于 2.婴儿T细胞分化导致组织中的效应器反应，但降低 持久化TRM的产生。这些发现表明了一种总体假设，即婴儿的肺和小 肠道是早期T细胞启动和效应分化的主要部位，但这种反应是有限的 通过早期幼稚T细胞激活和分化的内在差异。将效应器响应限制为 粘膜部位，可能防止效应细胞过度激活和扩散到多个组织在 高抗原暴露的早期生命阶段。我们将阐述有关婴儿组织T细胞起源的假说 利用新的人类组织样本和幼鼠对两个目标的细胞反应进行协调研究 感染的模型。在Aim1中，我们将确定粘膜启动在效应和记忆分化中的作用 并检验幼稚T细胞原位启动发生在粘膜部位的假说 在婴儿期，与成人反应相比，LN参与较少。在目标2中，我们将阐明内在的 婴儿接触病原体导致记忆T细胞发育减少的机制，并测试 婴儿效应器被转录编程为死亡而不是存活的假说以及 转录因子表达和/或生存因子的调节可能促进婴儿TRM的产生。 拟议研究的结果将揭示促进婴儿T细胞分化和 通过组织靶向产生记忆。

Project Summary Immune responses in mucosal and barrier tissues are critical for protecting an individual from the myriad pathogens that infect these sites, and long-term protection can be maintained in situ by subsets of T lymphocytes called tissue-resident memory T cells (TRM). At birth, humans emerge from a largely sterile environment to one where they rapidly encounter multiple, diverse antigens, particularly in the respiratory and digestive tracts. The lungs and intestines are also sites where infants are highly susceptible to infectious pathogens and can develop life-threatening diseases. This vulnerability of infants to infectious disease has been previously attributed to the immaturity of their immune systems; however, the distinct properties of infant immune responses are not fully defined, and have been largely characterized in circulation or lymphoid tissues and not in key mucosal sites. Identifying the mechanisms by which infants can mediate anti-pathogen immune responses, generate long-term memory, and maintain homeostasis, is essential for designing new strategies for vaccination and immunomodulation at the earliest life stage. We initiated studies on infant immunity (supported by the NIAID infant program) four years ago through investigations of T cell differentiation in human infant tissue samples from organ donors, airway samples from infants with viral infection, and in a mouse model of influenza virus infection. Together our findings have revealed novel aspects of early life immunity including: 1. that infant memory T cells are found predominantly in lungs and intestines and not in the periphery, and 2. that differentiation of infant T cells lead to effector responses in tissues, but reduced generation of persisting TRM. These findings suggest an overall hypothesis that infant lungs and small intestines are major sites for early T cell priming and effector differentiation, but that such responses are limited by intrinsic differences in early naïve T cell activation and differentiation. Confining effector responses to mucosal sites, may prevent hyperactivation and dissemination of effector cells to multiple tissues during the early life stages of high antigen exposure. We will address our hypotheses for the genesis of infant tissue T cell responses in two aims with coordinate investigations using novel human tissue samples and infant mouse models of infection. In Aim1, we will determine role of mucosal priming in differentiation of effector and memory T cells during infancy and test the hypothesis that in situ priming of naïve T cells occurs within mucosal sites during infancy with reduced LN involvement compared to adult responses. In aim 2, we will elucidate intrinsic mechanisms for reduced development of memory T cells from infant pathogen exposure, and test the hypothesis that infant effectors are transcriptionally programmed to die rather than persist and whether modulation of transcription factor expression and/or survival factors may promote infant TRM generation. Results from the proposed studies will reveal novel mechanisms for promoting infant T cell differentiation and memory generation through tissue targeting.