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

• 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
• 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

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.

项目总结/摘要 即使在没有T细胞的情况下，记忆性CD 8 T细胞区室也可以被炎症因子激活 受体信号这个过程被称为记忆T细胞的旁观者激活， 不同的感染。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CD 8 T细胞在控制早期病原体中起着至关重要的作用， 感染后复制。我们证明了旁观者激活的记忆性CD 8 T细胞表达 颗粒酶B，并且可以以TCR非依赖性的先天性方式直接杀死靶细胞。与他们的 对于感染后宿主免疫的有益作用，我们最近的数据提供了强有力的证据， 旁观者激活的T细胞通过消除抗原降低疫苗接种后的抗原可用性， 递呈细胞。 我们建议测试这一假设，即旁观者激活的记忆CD 8 T细胞发挥了基本作用， 在直接控制细胞和体液免疫反应的大小方面， 预防针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应答，并确定 导致疫苗接种后抗原可用性降低的机制。我们将使用一个小鼠模型 系统来定义靶细胞消除和原代人T细胞离体 确保与人类健康直接相关。 这一提议是非常重要的，因为解决旁观者激活的记忆T细胞在免疫系统中的作用是非常重要的。 疫苗背景是最重要和最紧迫的细胞免疫学研究课题之一， 通过在有感染风险和最易感染的特定人群中接种疫苗，实现有效免疫。 该提议具有高度创新性，因为我们确定NKG 2D是该过程中的关键分子， 设计了一种新的拮抗剂，旨在通过抑制旁观者激活的CD 8 T细胞来增强疫苗的效力。 细胞功能我们提出的实验清楚地定义了旁观者激活对随后的影响。 免疫反应，并提供一个新的战略，提高疫苗的效力。