Understanding the functional agility of effector memory CD8 T cells

项目总结/摘要 具有不同功能特征的记忆性CD 8 T细胞在感染后产生，或 次免疫我们之前定义了CD 62 Llo效应记忆中的T细胞群， 表达高水平效应分子并持续存在于细胞中的细胞间质中。 记忆阶段尽管随着时间的推移，在无特定病原体的小鼠中，LLEC趋于减弱， 数量，它们代表了“脏小鼠”中CD 8记忆T细胞的相当大一部分， 控制二级和三级内存池。重要的是，我们之前的工作表明， 这些“长寿效应细胞”（LLEC）是介导免疫应答的最强大的记忆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可能通过多个基因的独特表达来实现这一点。 NK细胞相关受体以及趋化因子和运输分子， 它们在稳定状态下严格定位于脉管系统。在本提案中，我们将确定： 1)如果LLEC通过外渗或从它们的组织中参与组织引发的感染， 2）如果NK细胞受体调节LLEC功能，以及3）如果 LLEC亚群因其持久性而在炎症期间独特地繁荣。我们的提案利用了 最近的转录分析沿着创新的小鼠模型和技术方法， 了解控制循环记忆T细胞群如何介导保护性T细胞的信号 免疫力我们预测我们的研究将揭示产生强大记忆的新考虑因素 T细胞功能，最终导致改进的疫苗接种和免疫治疗方法。

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.