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: 6731215
• 负责人: RANCE E BERG
• 金额: $ 5.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731215
• 关键词: Listeria; Listeria infections; T cell receptor; biological signal transduction; cell membrane; cellular immunity; cytokine; cytokine receptors; cytotoxic T lymphocyte; gene expression; genetically modified animals; immunomagnetic separation; immunoregulation; interferon gamma; interleukin 12; laboratory mouse; microarray technology; polymerase chain reaction; postdoctoral investigator; tissue /cell culture

DESCRIPTION (provided by the applicant): We have recently uncovered a role for CD8+ T cells in the innate immune response and this proposal is designed to understand the mechanisms by which CD8+ T cells contribute to innate immunity. Specifically, we have shown that a subset of CD8+ T cells rapidly secrete IFN-gamma in response to infection with Listeria monocytogenes (LM). This IFN-? secretion is antigen/TCR independent and is promoted by cytokine stimulation. The specific aims are as follows: I) To characterize the CD8+ T cells that secrete IFN-gamma, II) To determine the contribution of CD8+ T cells in innate immune responses, and III) To use microarray analysis to determine which genes are involved in controlling responsiveness of CD8+ T cells to IL-12 and IL-18. To achieve specific aim I, we will further characterize the cell surface phenotype of the CD8+ T cells secreting IFN-? with regard to their activation/memory status. Furthermore, we will determine the levels of the cytokine receptors responsible for inducing IFN-gamma secretion and see if this correlates with responsiveness. Specific aim II will require in vivo studies to analyze what role CD8+ T cells play in the innate immune response. Once a surface phenotype has been established from specific aim I, we will use this knowledge to transfer purified populations of CD8+ T cells into IFN gamma, knock-out mice to overcome the natural defect in IFN-gamma which results in mortality upon infection with LM. Using microarray analysis for specific aim III will allow us to identify genes which are involved in controlling the responsiveness of CD8+ T cells to innate stimulation mediated by IL-12 and IL-18. The results of the experiments outlined in this proposal will advance our knowledge concerning the role of CD8+ T cells in innate responses to bacteria, viruses and tumors. Armed with this knowledge, we can use these CD8+ T cells to help combat infectious diseases and tumors early in the disease state.

描述（由申请人提供）：我们最近发现了 CD8+ T 细胞在先天免疫反应中的作用，该提案旨在了解 CD8+ T 细胞促进先天免疫的机制。具体来说，我们已经证明，CD8+ T 细胞的一个子集会快速分泌 IFN-γ，以响应单核细胞增生李斯特氏菌 (LM) 的感染。这个干扰素-?分泌不依赖于抗原/TCR，并通过细胞因子刺激促进。具体目标如下：I) 表征分泌 IFN-γ 的 CD8+ T 细胞，II) 确定 CD8+ T 细胞在先天免疫反应中的贡献，以及 III) 使用微阵列分析确定哪些基因参与控制 CD8+ T 细胞对 IL-12 和 IL-18 的反应。为了实现特定目标I，我们将进一步表征分泌IFN-α的CD8+T细胞的细胞表面表型。关于它们的激活/记忆状态。此外，我们将确定负责诱导 IFN-γ 分泌的细胞因子受体的水平，并看看这是否与反应性相关。具体目标 II 需要体内研究来分析 CD8+ T 细胞在先天免疫反应中发挥的作用。一旦从特定目标 I 建立了表面表型，我们将利用这些知识将纯化的 CD8+ T 细胞群转移到 IFN γ 敲除小鼠中，以克服 IFN γ 的天然缺陷，该缺陷会导致 LM 感染后死亡。使用特定目标 III 的微阵列分析将使我们能够识别参与控制 CD8+ T 细胞对 IL-12 和 IL-18 介导的先天刺激的反应性的基因。本提案中概述的实验结果将增进我们对 CD8+ T 细胞在对细菌、病毒和肿瘤的先天反应中的作用的认识。有了这些知识，我们就可以利用这些 CD8+ T 细胞在疾病早期帮助对抗传染病和肿瘤。