Role of CD8+ T Cells in Innate Immune Responses

描述（由申请人提供）：我们最近发现了CD 8 + T细胞在先天免疫应答中的作用，该提议旨在了解CD 8 + T细胞促进先天免疫的机制。具体地说，我们已经表明，一个子集的CD 8 + T细胞迅速分泌IFN-γ的单核细胞增生李斯特菌（LM）感染的反应。这个干扰素？分泌是抗原/TCR非依赖性的，并由细胞因子刺激促进。具体目的如下：I）表征分泌IFN-γ的CD 8 + T细胞，II）确定CD 8 + T细胞在先天免疫应答中的贡献，和III）使用微阵列分析来确定哪些基因参与控制CD 8 + T细胞对IL-12和IL-18的应答。为了实现具体的目标我，我们将进一步表征分泌IFN-γ的CD 8 + T细胞的细胞表面表型？关于它们的激活/存储器状态。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，看看这是否与反应性相关。具体目标II将需要体内研究来分析CD 8 + T细胞在先天性免疫应答中起什么作用。一旦从特定目标I建立了表面表型，我们将利用这一知识将纯化的CD 8 + T细胞群转移到IFN γ敲除小鼠中，以克服IFN-γ的天然缺陷，该缺陷导致LM感染后死亡。使用针对特定目标III的微阵列分析将使我们能够鉴定参与控制CD 8 + T细胞对IL-12和IL-18介导的先天刺激的反应性的基因。该提案中概述的实验结果将推进我们对CD 8 + 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，我们可以使用这些CD 8 + T细胞来帮助在疾病早期对抗传染病和肿瘤。

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.