Mechanisms limiting neonatal immunity

限制新生儿免疫力的机制

基本信息

批准号：
8697640
负责人：
Brian David Rudd
金额：
$ 38.6万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

项目摘要

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.

描述（申请人证明）：新生儿特别容易受到细胞内病原体的影响。在冰中的一级和记忆CD8+ T细胞中，预后数据表明，新生儿CD8+ T细胞可能会形成不良的记忆力，而不是由于响应的不足，因此是范围的范围。新生儿记忆CD8+ T细胞的差异。在第二个目标中，新生儿CD8+ T细胞本质上是不同的。细胞动力学，我们将剖析关键的细胞内部环境差异，在维护上纯化tenatal cd8+ t合同的每个阶段）。将确定如何最好地改善CD8+ T细胞在开发阶段。