Differentiation of pathogen-specific memory CD8 T cell responses

病原体特异性记忆 CD8 T 细胞反应的分化

• 批准号: 9814211
• 负责人: VLADIMIR P BADOVINAC
• 金额: $ 23.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-22 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814211
• 关键词: Antigens; Antitumor Response; Biological; Breeding; CD8-Positive T-Lymphocytes; Cell Maintenance; Characteristics; Clinical; Communicable Diseases; Comparative Study; Complex; Data; Dose; Epigenetic Process; Generations; Genetic; Genetic Transcription; Genetic Variation; Genome; Goals; Human; Immune; Immune response; Immunity; Immunology; Inbred Mouse; Inbred Strains Mice; Inbreeding; Individual; Infection; Kinetics; Maintenance; Mediating; Memory; Mouse Strains; Mus; Outcome; Phenotype; Play; Population; Population Heterogeneity; Reproducibility; Role; Route; Single Nucleotide Polymorphism; Specificity; T cell differentiation; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Techniques; Testing; Time; Vaccination; Vaccine Design; Variant; Virus Diseases; adaptive immune response; base; cancer immunotherapy; cohort; mouse model; pathogen; response; tool

Abstract Memory CD8 T cells play a critical role in mediating protection against infection by intracellular pathogens or in anti-tumor responses. Since durable protective immunity is the goal of vaccination, understanding the mechanisms that regulate naïve-to-memory CD8 T cell differentiation and long-term maintenance of CD8 T cell memory is critical for rational design of vaccines. Technical advances have allowed tracking of some, but not all, CD8 T cells responding to infection, and a body of information now exists describing phenotypic/functional/transcriptional/epigenetic changes that occur in CD8 T cells of known Ag-specificity during their activation, expansion, and memory generation in mice. However, current mouse models of infections may underrepresent the complexity of human immune responses. We recently described a technique that can be used to track pathogen-specific CD8 T cell responses in any mouse and noted substantial discord in the magnitude/kinetics/memory CD8 T cell differentiation in individual outbred mice following infection. Therefore, one can argue that given the variability of immune responses and clinical outcomes generally observed in human population, limited number of inbred mouse models cannot fully recapitulate the range of immune phenotypes expressed across diverse humans. Collaborative Cross (CC) mouse model could represent an exciting approach to examine the biological networks and genetic factors that govern divergent CD8 T cell outcomes following infection. Commercially available CC lines, derived using a funnel breeding strategy with eight founder strains, contain defined single nucleotide polymorphisms and insertions or deletions that results in vast genetic diversity between lines. This is similar to outbred cohorts, however, the progeny within established lines are inbred allowing for precise analyses, reproducibility and comparative studies. Thus, the goal of this proposal is to start decoding variability of pathogen-specific memory CD8 T cell differentiation observed in genetically distinct hosts using CC lines. Proposal is based on exciting preliminary data that identified CC lines in which memory CD8 T cell development deviates from `canonical' memory CD8 T cell responses observed in inbred B6 mice after viral infection. We will test the overall hypothesis that naïve-to-memory CD8 T cell differentiation to infection is complex and potentially controlled by host specific biological and/or genetic factors. Aims proposed are: SA1 Define factors controlling differentiation of memory CD8 T cells in defined strains of CC mice; SA2 Identify genetically variant genome regions associated with variance in memory CD8 T cell differentiation.

抽象的 记忆 CD8 T 细胞在介导针对细胞内病原体感染的保护或在 抗肿瘤反应。由于持久的保护性免疫力是疫苗接种的目标，因此了解 调节初始记忆 CD8 T 细胞分化和 CD8 T 细胞长期维持的机制 记忆对于疫苗的合理设计至关重要。技术进步已经允许追踪一些，但还不能 所有 CD8 T 细胞对感染作出反应，现在存在大量信息描述 已知 Ag 特异性的 CD8 T 细胞中发生的表型/功能/转录/表观遗传变化 在小鼠体内激活、扩展和记忆生成过程中。然而，目前的鼠标模型 感染可能低估了人类免疫反应的复杂性。我们最近描述了一个 该技术可用于追踪任何小鼠中病原体特异性 CD8 T 细胞反应，并指出 个体远交小鼠中 CD8 T 细胞分化的幅度/动力学/记忆显着不一致 感染后。因此，人们可以认为，鉴于免疫反应和临床的可变性 在人类群体中普遍观察到的结果，有限数量的近交小鼠模型不能完全 概括了不同人类表达的免疫表型范围。协作交叉 (CC) 小鼠模型可能代表一种令人兴奋的方法来检查生物网络和遗传因素 控制感染后不同的 CD8 T 细胞结果。市售 CC 线，使用 具有八个创始菌株的漏斗育种策略，包含明确的单核苷酸多态性和 插入或缺失导致品系之间存在巨大的遗传多样性。这类似于近亲繁殖群体， 然而，已建立的品系内的后代是近交的，可以进行精确的分析、再现性和 比较研究。因此，该提案的目标是开始解码病原体特异性记忆的变异性 使用 CC 系在遗传不同的宿主中观察到 CD8 T 细胞分化。提案基于令人兴奋的 初步数据确定了记忆 CD8 T 细胞发育偏离“规范”的 CC 系 病毒感染后在近交 B6 小鼠中观察到的记忆 CD8 T 细胞反应。我们将测试整体 假设从幼稚到记忆的 CD8 T 细胞向感染的分化是复杂的，并且可能由以下因素控制： 宿主特定的生物和/或遗传因素。提议的目标是： SA1 定义控制分化的因素 特定品系 CC 小鼠中记忆 CD8 T 细胞的数量； SA2 识别遗传变异基因组区域 与记忆 CD8 T 细胞分化的差异相关。