Mechanisms limiting neonatal immunity

限制新生儿免疫力的机制

• 批准号: 9015341
• 负责人: Brian David Rudd
• 金额: $ 37.13万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9015341
• 关键词: Acute; Adopted; Adoptive Transfer; Adult; Animal Model; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Cycle; Cell division; Cells; Cues; Data; Defect; Derivation procedure; Development; Disease; Environment; Environmental Risk Factor; Experimental Models; Generations; Goals; Health; Hematopoietic stem cells; Homeostasis; Immune; Immunity; Impairment; Infection; Interleukin-15; Interleukin-7; Intrinsic factor; Knowledge; Life; Maintenance; Measures; Memory; Modeling; Mus; Neonatal; Peripheral; Phenotype; Population; Positioning Attribute; Proliferating; Rest; Series; Staging; Statistical Data Interpretation; Statistical Models; Stem cells; Streptococcus; T cell response; T-Cell Development; T-Lymphocyte; Testing; Vaccination; Vaccines; aged; cell behavior; cytokine; design; experience; fetal; improved; insight; neonatal immunity; neonate; pathogen; programs; research study; response

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（由申请人提供）：新生儿特别容易受到细胞内病原体的影响，导致新生儿 CD8+ T 细胞反应不良的基本机制尚不清楚，因此不可能开发出治疗方法和疫苗来促进生命早期有效的 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，并表征了新生和成年小鼠中原代和记忆CD8+ T细胞的生成，出乎意料的是，初步数据表明新生CD8+ T细胞可能形成。记忆力差，不是因为无法做出反应，而是因为它们更快地进行终末分化。因此，该提案的目标是量化细胞内在和环境差异对新生儿记忆 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会改变感染后记忆 CD8+ T 细胞的生成和维持。第一个目标是确定记忆 CD8+ T 细胞的发育是否在生命早期发生改变。 ve 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源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 细胞的帮助）如何影响。新生记忆 CD8+ T 细胞的产生采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中的基本方法，并结合 T 细胞动力学的统计分析和建模，我们将 剖析新生儿 CD8+ T 细胞反应的每个阶段（例如扩张、收缩、维持）中存在的关键细胞内在和环境差异，从而找出导致 CD8+ T 细胞免疫力差以及最大化的最重要机制。最终，我们将确定通过修复这些缺陷可以获得的益处，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 细胞免疫提供关键见解。