Inflammation-driven T Cell Responses and their Dichotomous Effect on Host Immunity

炎症驱动的 T 细胞反应及其对宿主免疫的二分效应

基本信息

批准号：
10058804
负责人：
Martin Prlic
金额：
$ 27.32万
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：
2016-12-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058804
关键词：
Address Affect Age Antigen Presentation Antigen-Presenting Cells Antigens B-Lymphocytes Biological Models CD8-Positive T-Lymphocytes Cell Compartmentation Cell physiology Cells Cellular Immunology Communicable Diseases Cues Data Dendritic Cells Elderly Engineering Ensure Goals Granzyme Health Human Immune response Immunity Immunization Infection Inflammation Inflammatory Interleukin-12 Interleukin-15 Interleukin-18 Lead Ligands Measures Mediating Memory Memory B-Lymphocyte Morbidity - disease rate Mus Nature Outcome Phenotype Play Population Populations at Risk Process Receptor Signaling Reporting Research Role Signal Transduction T cell response T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Vaccination Vaccines Vulnerable Populations adaptive immune response antigen-specific T cells cell killing cytokine cytotoxic design experimental study improved inhibitor/antagonist innovation mortality mouse model novel pathogen perforin preservation response vaccine development vaccine efficacy vaccine response

项目摘要

PROJECT SUMMARY / ABSTRACT The memory CD8 T cell compartment can be activated by inflammatory cues even in the absence of a T cell receptor signal. This process is referred to as bystander-activation of memory T cells and has been observed following different infections. The contribution of these cells to host immunity was poorly understood until we recently reported that bystander-activated memory CD8 T cells play a crucial role in controlling early pathogen replication following infection. We demonstrated that bystander-activated memory CD8 T cells express granzyme B and can directly kill target cells in a TCR-independent, innate-like fashion. In stark contrast to their beneficial effect for host immunity following infection, our most recent data provide strong evidence that these bystander-activated T cells decrease antigen availability following vaccination by eliminating antigen- presenting cells. We propose to test the hypothesis that bystander-activated memory CD8 T cells play a fundamental and thus far unappreciated role in directly controlling the size of the cellular and humoral immune response following vaccination. We will determine which memory T cell subsets are capable of becoming bystander-activated, identify how bystander-activated T cells affect subsequent adaptive immune responses and define the mechanisms that lead to decreased antigen availability following vaccination. We will use a mouse model system to define the underlying mechanisms of target cell elimination and primary human T cells ex vivo to ensure direct relevance for human health. This proposal is highly significant because addressing the role of bystander-activated memory T cells in a vaccine context is one of the most significant and pressing cellular immunology research topics due to the inability to achieve effective immunity by vaccination in select populations at risk for and most susceptible to infections. This proposal is highly innovative because we identified NKG2D as a key molecule in this process and engineered a novel antagonist designed to enhance vaccine efficacy by inhibiting bystander-activated CD8 T cell function. Our proposed experiments clearly define the impact of bystander-activation on subsequent immune responses and to provide a new strategy for enhancing vaccine efficacy.

项目概要/摘要即使在没有 T 细胞的情况下，记忆 CD8 T 细胞区室也可以被炎症信号激活受体信号。这个过程被称为记忆 T 细胞的旁观者激活，并且已被观察到不同感染后。人们对这些细胞对宿主免疫的贡献知之甚少，直到我们最近报道，旁观者激活的记忆 CD8 T 细胞在控制早期病原体中发挥着至关重要的作用感染后的复制。我们证明旁观者激活的记忆 CD8 T 细胞表达颗粒酶 B 可以以不依赖于 TCR 的、先天性的方式直接杀死靶细胞。与他们形成鲜明对比感染后对宿主免疫产生有益影响，我们最新的数据提供了强有力的证据表明这些旁观者激活的 T 细胞通过消除抗原来降低疫苗接种后抗原的可用性呈现细胞。我们建议检验旁观者激活的记忆 CD8 T 细胞发挥基础作用的假设，从而在直接控制细胞和体液免疫反应大小方面的作用远未被认识到疫苗接种。我们将确定哪些记忆 T 细胞亚群能够被旁观者激活，确定旁观者激活的 T 细胞如何影响随后的适应性免疫反应并定义导致疫苗接种后抗原可用性降低的机制。我们将使用鼠标模型系统来定义靶细胞消除和原代人 T 细胞离体的基本机制确保与人类健康直接相关。这一提议非常重要，因为它解决了旁观者激活的记忆 T 细胞在疫苗背景是最重要和最紧迫的细胞免疫学研究课题之一，因为无法通过在特定的有感染风险和最易感染人群中接种疫苗来获得有效的免疫力。该提案具有高度创新性，因为我们确定 NKG2D 是该过程中的关键分子，并且设计了一种新型拮抗剂，旨在通过抑制旁观者激活的 CD8 T 来增强疫苗功效细胞功能。我们提出的实验清楚地定义了旁观者激活对后续的影响免疫反应并提供增强疫苗功效的新策略。