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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要具有不同功能特征的记忆 CD8 T 细胞在感染或我们之前定义了 CD62Llo 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隔室尽管随着时间的推移，在无特定病原体的小鼠中，LLEC 往往会减弱。数字，它们代表了“肮脏小鼠”中 CD8 记忆 T 细胞的很大一部分，重要的是，我们之前的工作表明，这些“长寿命效应细胞”(LLEC) 是介导最强大的记忆 T 细胞我们最近对全身病毒和细菌病原体进行抗原特异性清除。测序数据表明 LLEC 可以通过多种独特的表达来实现这一目标 NK 细胞相关受体以及可能强制执行的趋化因子和贩运分子在稳定状态下它们严格定位于脉管系统。 1）如果 LLEC 通过外渗或来自其自身参与组织引发的感染血管内的位置，2) NK 细胞受体是否调节 LLEC 功能，以及 3) 如果 LLEC 子集因其持久性而在炎症期间独特地蓬勃发展。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 细胞群如何介导保护性的信号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，最终导致疫苗接种和免疫治疗方法的改进。