Immunoprotective Properties of Tissue-resident Memory T Cells in Mice and Humans within Mucosal Sites

小鼠和人类粘膜部位组织驻留记忆 T 细胞的免疫保护特性

• 批准号: 10641296
• 负责人: Jennifer M Lund
• 金额: $ 14.64万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641296
• 关键词: Immunoprotective; Properties; Tissue; resident; Memory

PROJECT SUMMARY The goal of this project is to thoroughly define the immunoprotective role of tissue resident T cells (TRM) against viral pathogens. Underlying our proposed experiments is the idea that TRM have the ability to rapidly contain viruses within microscopic tissue microenvironments over rapid timeframes. Therefore, we focus on critical features of TRM such as gene expression profile, homeostasis, apoptosis and trafficking, before, during and at multiple time points following clearance of a mucosal virus within microscopic sites of infection. In Aim 1, we propose studying the specific role of antigen specific and non-specific tissue resident CD8+ T-cells, as well as tissue resident CD4+ T-cells, during rapid containment of virus in murine vaginal tissue microenvironments. In Aim 2, we interrogate the infection microenvironments in mice following clearance of virus with the specific goal of measuring rates of TRM apoptosis, homeostasis, intra-mucosal trafficking and activation status over time frames of weeks. These parameters will ultimately be evaluated for their relationship to waning protection following re-exposure to virus at various time intervals. In Aim 3, we employ human studies to assess kinetics of genital HSV-2 containment and cytokine response within single infection microenvironments, as well as localization of TRM at multiple time points following viral containment. These studies are designed to verify relevance of specific components of the mouse model to human immunity, and to provide data for design and validation of mathematical models, the goal of which is to identify a threshold quantity and spatial distribution of TRM necessary for rapid viral containment. The model will also help identify why TRM do not provide comprehensive protection against reactivating HSV-2.

项目摘要 该项目的目的是彻底定义组织驻留T细胞（TRM）的免疫保护作用 病毒病原体。我们提出的实验的基础是TRM具有快速包含的想法 在快速时期内，微观组织微环境中的病毒。因此，我们专注于批判 TRM的特征，例如基因表达谱，稳态，凋亡和运输，之前，之中和处 在微观感染部位清除粘膜病毒后多个时间点。在AIM 1中，我们 建议研究抗原特异性组织和非特异性组织常驻CD8+ T细胞的特定作用，以及 在鼠阴道组织微环境中快速遏制病毒的过程中，组织驻留的CD4+ T细胞。在 AIM 2，我们询问与特定病毒清除病毒后小鼠的感染微环境 测量TRM凋亡，稳态，粘膜内贩运和激活状态的目标 几周的框架。这些参数最终将与它们与保护的关系进行评估 在以各种时间间隔重新暴露病毒后。在AIM 3中，我们采用人类研究来评估动力学 单一感染微环境中的生殖器HSV-2遏制和细胞因子反应以及 病毒遏制后多个时间点的TRM定位。这些研究旨在验证 鼠标模型的特定组件与人类免疫力的相关性，并提供设计数据和 验证数学模型，其目的是确定阈值数量和空间分布 快速病毒遏制所需的TRM。该模型还将帮助确定为什么TRM不提供 综合保护防止HSV-2。