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.

项目摘要/摘要 即使在没有T细胞的情况下，记忆中的CD8 T细胞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，已经观察到 在不同的感染之后。直到我们对这些细胞对宿主免疫的贡献知之甚少 新近报道，旁观者激活的记忆CD8 T细胞在控制早期病原体中起着至关重要的作用 感染后的复制。我们证明了旁观者激活的记忆CD8 T细胞表达 颗粒酶B，可以不依赖于TCR的、先天的方式直接杀死靶细胞。与他们形成鲜明对比的是他们 对宿主免疫的有益影响感染后，我们的最新数据提供了强有力的证据，这些 旁观者激活的T细胞通过清除抗原而降低疫苗接种后的抗原可用性- 呈现细胞。 我们建议检验旁观者激活的记忆CD8T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的大小方面的作用远未被认识到 接种疫苗。我们将确定哪些记忆T细胞亚群能够成为旁观者激活的， 确定旁观者激活的T细胞如何影响后续的适应性免疫反应，并定义 疫苗接种后导致抗原可获得性降低的机制。我们将使用一个小鼠模型 确定靶细胞消除和体外原代人类T细胞的潜在机制的系统 确保与人类健康直接相关。 这一建议非常有意义，因为解决旁观者激活的记忆T细胞在 疫苗背景是细胞免疫学研究中最重要和最紧迫的课题之一，因为它无法 通过接种疫苗，在有感染风险和最易受感染的特定人群中实现有效免疫。 这一提议具有很高的创新性，因为我们确定NKG2D是这一过程中的关键分子，并且 设计了一种新的拮抗剂，旨在通过抑制旁观者激活的CD8T来增强疫苗效力 细胞功能。我们提出的实验清楚地定义了旁观者激活对后续 并为提高疫苗效力提供一种新的策略。