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: 9306765
• 负责人: Jennifer M Lund
• 金额: $ 83.03万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306765
• 关键词: Address; Animal Model; Antigens; Apoptosis; Architecture; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Count; Cell Density; Cell physiology; Cells; Characteristics; Clinical; Communicable Diseases; Computer Simulation; Containment; Cues; Data; Disease; Drug or chemical Tissue Distribution; Event; Exposure to; Future; Gene Expression Profile; Gene Expression Profiling; Goals; Heterogeneity; Homeostasis; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; Immunologics; Immunology; Infection; Intervention; Investigation; Kinetics; Lead; Longevity; Maintenance; Mathematics; Measures; Mediating; Mediator of activation protein; Microscopic; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Outcome; Population; Property; Recording of previous events; Research Personnel; Role; Simplexvirus; Site; Spatial Distribution; System; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Translating; Vaccine Design; Vaccines; Vagina; Validation; Viral; Virus; Virus Diseases; Woman; base; cell mediated immune response; cytokine; design; experience; experimental study; frontier; genital herpes; human tissue; mathematical model; mouse model; mucosal site; pathogen; protective effect; response; time interval; trafficking

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.

项目概要 该项目的目标是彻底确定组织驻留 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 能够快速遏制 在快速的时间范围内微观组织微环境中的病毒。因此，我们重点关注关键 TRM 的特征，例如之前、期间和当时的基因表达谱、稳态、细胞凋亡和运输 在微观感染部位内清除粘膜病毒后的多个时间点。在目标 1 中，我们 建议研究抗原特异性和非特异性组织驻留 CD8+ T 细胞的具体作用，以及 组织驻留 CD4+ T 细胞，在小鼠阴道组织微环境中快速遏制病毒期间。在 目标 2，我们用特定的病毒清除后小鼠的感染微环境 测量 TRM 凋亡率、稳态、粘膜内运输和激活状态随时间的变化的目标 几周的框架。最终将评估这些参数与减弱保护的关系 在不同时间间隔再次接触病毒后。在目标 3 中，我们采用人体研究来评估动力学 单一感染微环境中生殖器 HSV-2 遏制和细胞因子反应的影响，以及 病毒遏制后多个时间点的 TRM 定位。这些研究旨在验证 小鼠模型的特定组成部分与人类免疫的相关性，并为设计和提供数据 数学模型的验证，其目标是确定阈值数量和空间分布 快速遏制病毒所必需的 TRM。该模型还将有助于确定为什么 TRM 不提供 全面防止 HSV-2 重新激活。