Mechanisms limiting neonatal immunity

描述(申请人提供)：新生儿特别容易受到细胞内病原体的影响。新生儿产生CD8+T细胞反应差的基本机制尚不清楚，因此不可能开发出治疗和疫苗来促进早期有效的CD8+T细胞免疫。因此，我们建立了一种新生儿感染的动物模型，并研究了新生和成年小鼠原始和记忆性CD8+T细胞的生成。出乎意料的是，初步数据表明，新生儿CD8+T细胞可能会形成糟糕的记忆，这不是因为他们没有反应能力，而是因为他们更快地变得更快地进入终末分化。因此，这项建议的目标是量化细胞固有和环境差异对新生儿记忆CD8+T细胞受损的影响程度。我们的总体假设是，T细胞复制和动态平衡的差异改变了感染后记忆CD8+T细胞的产生和维持。在第一个目标中，将确定早期生命中记忆CD8+T细胞的发育是否因为新生儿CD8+T细胞在感染前本质上的不同(由于广泛的动态平衡增殖或来自不同年龄的造血干细胞)而改变。在第二个目标中，我们将确定环境差异(动态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 剖析在新生儿CD8+T细胞反应的每个阶段(如扩张、收缩、维持)存在的关键细胞-内在和环境差异。在这样做的过程中，将确定导致CD8+T细胞免疫力低下的最重要机制，以及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最好地在发育的关键阶段提高CD8+T细胞免疫提供关键的见解。

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.