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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结该项目的目标是彻底确定组织驻留T细胞(TRM)对病毒病原体。我们提议的实验背后是这样一个想法，即TRM有能力迅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，我们将重点放在关键 TRM的特征，如基因表达谱、稳态、凋亡和转运，前、中和在在微小感染部位的粘膜病毒清除后的多个时间点。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细胞的特殊作用，以及在小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……里面目的2.检测病毒清除后小鼠的感染微环境。测量TRM凋亡率、内稳态、粘膜内转运和随时间变化的激活状态的目标以周为单位。这些参数最终将根据它们与减弱保护的关系进行评估在以不同的时间间隔再次暴露于病毒之后。在目标3中，我们使用人体研究来评估动力学单一感染微环境中生殖器HSV-2的抑制和细胞因子反应，以及病毒控制后多个时间点的TRM定位。这些研究旨在验证小鼠模型的特定组件与人类免疫的相关性，并为设计和提供数据验证数学模型，其目标是确定临界数量和空间分布快速遏制病毒所需的TRM。该模型还将有助于确定为什么TRM不能提供防止HSV-2重新激活的全面保护。