Role of CD8+ T Cells in Innate Immune Responses

CD8 T 细胞在先天免疫反应中的作用

• 批准号: 6908463
• 负责人: RANCE E BERG
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908463
• 关键词: Listeria; Listeria infections; T cell receptor; biological signal transduction; cell migration; cell population study; cellular immunity; cytotoxic T lymphocyte; flow cytometry; genetically modified animals; helper T lymphocyte; immunocytochemistry; immunologic memory; interferon gamma; interleukin 12; interleukin 18; laboratory mouse; leukocyte activation /transformation; microarray technology; microorganism immunology; natural killer cells; polymerase chain reaction; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): This proposal is aimed at understanding the development, rapid function, and localization of CD8+ T cells that respond in the absence of cognate antigen during bacterial infections, with the hypothesis that CD8+ T cells are important contributors to the early, innate production of IFN-gamma. The specific aims are: I: To analyze the survival, localization and protective ability of memory CD8+ T cells vs. NK cells during a Listeria monocytogenes (LM) infection. In this aim we will dissect the differences in protective ability between NK and memory CD8+ T cells responding to LM in a non-antigen specific fashion. We will use immunocytochemistry to analyze the location of the responding populations of transferred cells within the organs targeted by LM infection. In addition, the ability of memory CD8+ T and NK cells to survive after responding to LM will be measured using immunocytochemistry and flow cytometry. II: To determine the role of CD8+ T cells in aiding in the polarization of CD4+ T cells. Our data shows that memory CD8+ T cells rapidly secrete IFN-gamma independent of cognate antigen and thus play an important role in the innate immune response, which is essential in promoting TH1 development through the secretion of cytokines. We will now directly test the ability of CD8+ T cells and NK cells to influence TH1 development by secreting IFN-gamma using co-transfer protocols to analyze the polarization of CD4+ T cells in response to pathogens. III: To analyze the effects of IL-12 and IL-18 on naive and effector/memory CD8+ T cells. In the first part of this aim, we will determine which cytokines, if any, are required in order to establish IL-12/IL-18 responsiveness during the transition of naive CD8+ T cells into primed, effector cells. In the second part of the aim, we will determine the functional outcomes of signaling through the IL-12 and IL-18 receptors and compare that with signaling through the TCR using microarray analysis and real-time RT-PCR. These studies will further our understanding of innate immune responses to pathogens mediated by CD8+ T cells and allow us to better combat infectious diseases.

描述（由申请人提供）：本提案旨在了解细菌感染期间在缺乏同源抗原的情况下做出反应的 CD8+ T 细胞的发育、快速功能和定位，并假设 CD8+ T 细胞是早期、先天产生 IFN-γ 的重要贡献者。具体目标是： I：分析单核细胞增生李斯特菌 (LM) 感染期间记忆 CD8+ T 细胞与 NK 细胞的存活、定位和保护能力。为此，我们将剖析 NK 细胞和记忆 CD8+ T 细胞以非抗原特异性方式响应 LM 的保护能力的差异。我们将使用免疫细胞化学来分析 LM 感染目标器官内响应的转移细胞群的位置。此外，将使用免疫细胞化学和流式细胞术测量记忆 CD8+ T 和 NK 细胞对 LM 做出反应后的存活能力。 II：确定 CD8+ T 细胞在帮助 CD4+ T 细胞极化中的作用。我们的数据表明，记忆 CD8+ T 细胞快速分泌独立于同源抗原的 IFN-γ，因此在先天免疫反应中发挥重要作用，这对于通过分泌细胞因子促进 TH1 发育至关重要。我们现在将使用共转移方案直接测试 CD8+ T 细胞和 NK 细胞通过分泌 IFN-γ 影响 TH1 发育的能力，以分析 CD4+ T 细胞对病原体反应的极化。 III：分析IL-12和IL-18对初始和效应/记忆CD8+T细胞的影响。在该目标的第一部分中，我们将确定需要哪些细胞因子（如果有），以便在幼稚 CD8+ T 细胞转变为引发的效应细胞期间建立 IL-12/IL-18 反应性。在目标的第二部分中，我们将确定通过 IL-12 和 IL-18 受体发出信号的功能结果，并使用微阵列分析和实时 RT-PCR 将其与通过 TCR 发出的信号进行比较。这些研究将进一步加深我们对 CD8+ T 细胞介导的针对病原体的先天免疫反应的理解，并使我们能够更好地对抗传染病。