Understanding the functional agility of effector memory CD8 T cells

了解效应记忆 CD8 T 细胞的功能敏捷性

• 批准号: 10296829
• 负责人: Sara Elizabeth Hamilton Hart
• 金额: $ 55.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296829
• 关键词: Adoptive Transfer; Affect; Antigen Presentation; Antigens; Apoptosis; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; CD94 Antigen; CRISPR/Cas technology; Cell Compartmentation; Cell physiology; Cells; Characteristics; Cues; Cytokine Receptors; Data; Effector Cell; Endothelial Cells; Endothelium; Excision; Extravasation; Gene Expression; Gene Expression Profile; Generations; Genetic Transcription; Goals; Homing; Human; IFNAR1 gene; Immune response; Immunity; Immunization; Immunotherapy; Infection; Inflammation; Inflammatory; Knowledge; Ligands; Location; Lung; Maintenance; Measures; Mediating; Memory; Microbe; Mus; Natural Killer Cells; Phase; Population; Positioning Attribute; Process; Property; Rest; Signal Transduction; Site; Splenic Red Pulp; Stream; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Transgenic Organisms; Up-Regulation; Vaccination; Vascular Endothelial Cell; Work; acute infection; base; chemokine; chronic infection; experience; germ free condition; immunopathology; improved; in vivo; innovation; microbial; mouse model; neoplastic cell; novel; pathogen; pathogenic bacteria; pathogenic virus; prevent; receptor; response; single-cell RNA sequencing; trafficking; transcriptome sequencing; tumor

Project Summary/Abstract Memory CD8 T cells with varying functional characteristics are generated after infection or immunization. We previously defined a population of T cells within the CD62Llo effector memory compartment that express high levels of effector molecules and continue to persist into the memory phase. Although over time in specific pathogen free mice LLECs tend to wane in number, they represent a substantial fraction of CD8 memory T cells in ‘dirty mice’ and dominate the secondary and tertiary memory pools. Importantly, our prior work showed that these ‘long-lived effector cells’ (LLEC) are the most robust memory T cells for mediating antigen-specific clearance of systemic viral and bacterial pathogens. Our recent RNA sequencing data indicates that LLEC may achieve this through unique expression of multiple NK cell-associated receptors as well as chemokine and trafficking molecules that may enforce their strict localization to the vasculature at the steady state. In this proposal we will determine: 1) if LLECs participate in tissue-initiated infections through either extravasation or from their position within the vasculature, 2) if NK cell receptors modulate LLEC function, and 3) if the LLEC subset uniquely thrives during inflammation for its persistence. Our proposal leverages recent transcriptional analysis along with innovative mouse models and technical approaches to understand the signals governing how circulating memory T cell populations mediate protective immunity. We predict our studies will expose novel considerations for generating robust memory T cell function, ultimately leading to improved vaccination and immunotherapy approaches.

项目摘要/摘要 感染或感染后产生具有不同功能特征的记忆性CD8 T细胞 免疫接种。我们之前在CD62Llo效应器内存中定义了一组T细胞 表达高水平的效应器分子并继续持续进入 记忆阶段。尽管随着时间的推移，在无特定病原体的小鼠中，晶状体上皮细胞往往会减弱 数量，它们代表了CD8记忆T细胞的一个相当大的部分在‘脏老鼠’和 主宰二级和三级内存池。重要的是，我们之前的工作表明 这些“长寿效应细胞”(LLEC)是最健壮的记忆T细胞 抗原特异性清除全身性病毒和细菌病原体。我们最近的RNA 测序数据表明，LLEC可能通过多种基因的独特表达实现这一点 NK细胞相关受体以及趋化因子和运输分子可能 它们在稳定状态下严格定位于血管系统。在本提案中，我们将确定： 1)如果LLEC通过渗出或通过其自身的 在血管系统中的位置，2)如果NK细胞受体调节LLEC功能，3)如果 LLEC亚集因其持久性而在炎症期间独一无二地蓬勃发展。我们的提案充分利用了 最近的转录分析以及创新的小鼠模型和技术方法 了解控制循环记忆T细胞群如何调节保护作用的信号 豁免权。我们预测，我们的研究将揭示产生强健记忆的新考虑 T细胞功能，最终导致疫苗接种和免疫治疗方法的改进。