Mechanisms limiting neonatal immunity

描述（由申请人提供）：新生儿特别容易受到细胞内病原体的影响。新生儿中产生不良CD8+ T细胞应答的基本机制尚不清楚，因此无法开发治疗和疫苗来促进早期生命中有效的CD8+ T细胞免疫。因此，我们开发了一种新生儿感染的动物模型，并表征了新生儿和成年小鼠中初级和记忆CD8+ T细胞的产生。出乎意料的是，初步数据表明，新生儿CD8+ T细胞可能会形成记忆力差，不是因为无法响应，而是因为它们更快地成为终末分化。因此，本提案的目标是量化细胞内在和环境差异导致新生儿记忆CD8+ T细胞受损的程度。我们的总体假设是T细胞复制和稳态的差异改变了感染后记忆性CD8+ T细胞的产生和维持。在第一个目标中，将确定记忆性CD8+ T细胞发育在生命早期是否改变，因为幼稚新生儿CD8+ T细胞在感染前本质上是不同的（由于广泛的稳态增殖或来自不同年龄的造血干细胞）。在第二个目标中，我们将确定环境差异（稳态细胞因子的量，CD4+ T细胞帮助）如何影响新生儿记忆CD8+ T细胞的产生。使用在感染前将新生儿和成人CD8+ T细胞转移到新生儿和成人受体小鼠中的基本方法，结合T细胞动力学的统计分析和建模，我们将 剖析了新生儿CD8+ T细胞反应的每个阶段（例如扩增，收缩，维持）中存在的关键细胞内在和环境差异。在这样做时，将确定导致CD8+ T细胞免疫力低下的最重要机制以及通过修复这些缺陷可以获得的最大益处。最终，从这些研究中获得的知识将为如何在发育的关键阶段最好地提高CD8+ T细胞免疫力提供关键见解。

DESCRIPTION (provided by applicant): Neonates are particularly vulnerable to intracellular pathogens. The basic mechanisms underlying the generation of poor CD8+ T cell responses in neonates are unknown, making it impossible to develop treatments and vaccines to promote effective CD8+ T cell immunity in early life. Therefore, we developed an animal model of neonatal infection and characterized the generation of primary and memory CD8+ T cells in neonatal and adult mice. Unexpectedly, the preliminary data indicates that neonatal CD8+ T cells may form poor memory, not because of an inability to respond, but rather because they more quickly become terminally differentiated. Thus, the goal of this proposal is to quantify the extent to which cell-intrinsic and environmental differences contribute to impaired neonatal memory CD8+ T cells. Our overall hypothesis is that differences in T cell replication and homeostasis alter the generation and maintenance of memory CD8+ T cells following infection. In the first aim, it will be determined whether memory CD8+ T cell development is altered in early life because na¿ve neonatal CD8+ T cells are intrinsically different prior to infection (due o extensive homeostatic proliferation or derivation from different aged hematopoietic stem cells). In the second aim, we will determine how environmental differences (amount of homeostatic cytokines, CD4+ T cell help) influence the generation of neonatal memory CD8+ T cells. Using a basic approach of transferring neonatal and adult CD8+ T cells into neonatal and adult recipient mice prior to infection combined with statistical analysis and modeling of T cell dynamics, we will dissect out the key cell-intrinsic and environmental differences present during every stage of the neonatal CD8+ T cell response (e.g. expansion, contraction, maintenance). In doing so, the most important mechanisms contributing to poor CD8+ T cell immunity as well as the maximum amount of benefit that can be obtained by fixing these defects will be identified. Ultimately, knowledge gained from these studies will provide key insight into how best to improve CD8+ T cell immunity during critical stages of development.