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伤害。新生儿产生CD8+ T细胞不良反应的基本机制尚不清楚，因此不可能开发出在生命早期促进有效CD8+ T细胞免疫的治疗和疫苗。因此，我们建立了一种新生儿感染的动物模型，并描述了新生小鼠和成年小鼠原发性和记忆性CD8+ T细胞的产生。出乎意料的是，初步数据表明新生儿CD8+ T细胞可能形成较差的记忆，不是因为没有反应能力，而是因为它们更快地成为终末分化。因此，本研究的目标是量化细胞内在和环境差异对新生儿CD8+ T细胞记忆受损的影响程度。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，它将确定记忆性CD8+ T细胞的发育是否在生命早期被改变，因为新生儿的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（体内平衡细胞因子的数量，CD4+ T细胞的帮助）如何影响新生儿记忆性CD8+ T细胞的产生。利用在感染前将新生和成年CD8+ T细胞转移到新生和成年受体小鼠体内的基本方法，结合T细胞动力学的统计分析和建模，我们将

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.