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: 6646908
• 负责人: RANCE E BERG
• 金额: $ 4.81万
• 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/6646908
• 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(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，这项建议旨在了解CD8+T细胞促进先天免疫的机制。具体地说，我们已经证明了CD8+T细胞亚群在感染单核细胞增多性李斯特菌(Lm)后迅速分泌干扰素-γ。这个干扰素-？分泌不依赖于抗原/TCR，并由细胞因子刺激促进。其具体目的如下：1)确定分泌干扰素-γ的CD8+T细胞的特征；2)确定CD8+T细胞在天然免疫反应中的作用；3)利用基因芯片分析，确定哪些基因参与控制CD8+T细胞对IL-12和IL-18的应答。为了达到特定的目标I，我们将进一步鉴定分泌干扰素的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干扰素-γ分泌的细胞因子受体的水平，并看看这是否与反应性有关。特定目标II将需要进行体内研究，以分析CD8+T细胞在先天免疫反应中扮演的角色。一旦从特定的目标I确定了表面表型，我们将利用这一知识将CD8+T细胞的纯化群体转移到干扰素-γ基因敲除小鼠中，以克服干扰素-γ基因的天然缺陷，该缺陷会在感染LM时导致死亡。使用芯片分析的特定目的III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。这项建议中概述的实验结果将促进我们对CD8+T细胞在细菌、病毒和肿瘤的先天反应中所起作用的了解。有了这些知识，我们可以使用这些CD8+T细胞来帮助在疾病状态的早期与传染病和肿瘤作斗争。