Cellular Immune Responses to Respiratory Infection

对呼吸道感染的细胞免疫反应

• 批准号: 6867421
• 负责人: Martha Ann Alexander-Miller
• 金额: $ 32.29万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867421
• 关键词: Paramyxovirus; T cell receptor; antigen presenting cell; biological signal transduction; cellular immunity; cytokine; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; immune response; inflammation; laboratory mouse; leukocyte activation /transformation; lymph nodes; nitric oxide; pathologic process; respiratory infections; time resolved data; vaccinia virus; virus antigen; virus diseases; virus infection mechanism

The overall goal of our work is to identify mechanisms that regulate the activation and expansion of high avidity CD8+ T cells in response to virus infection in the lung. The difficulty in the development of protective vaccines for a number of clinically relevant respiratory viruses suggests that our understanding of the parameters that promote a protective immune response in the lung is incomplete. It has been shown previously that high avidity CD8+ T cells, which recognize low levels of antigenic peptide, are very potent immune cells since they recognize target cells at earlier times after infection and lyse infected cells more rapidly than low avidity cells. Thus the presence of high avidity cells is a key component of an optimal antiviral response. Our published data indicate that at early times after infection (d3) of the respiratory tract with the paramyxovirus simian virus 5 or the poxvirus vaccinia virus, the CD8+ T cell response is almost exclusively high avidity. However, at later times after infection (d5), low avidity cells are readily detected, comprising 50-60% of the total responding cells. Analysis of the CD8+ effector cells present in the lung identified a progressive loss in the ability of high avidity cells at this site to secrete IFN?, or lyse cells in response to stimulation. Loss of function selectively in high avidity cells is a novel form of immunosuppression. In aim 1, we will determine the extent of the functional deficit in the high avidity cells and whether low avidity cells demonstrate defects consistent with the early stages of the induction of nonresponsiveness. Subsequent studies will investigate the mechanism responsible for the change in function. Finally we will test the hypothesis that changes over time in the inflammatory environment present in the lung, e.g. cytokines and nitric oxide, are responsible for the induction of nonresponsiveness in high avidity cells. The studies in aim 2 analyze the generation of the anti-viral CD8+ T cell response in the draining lymph node. We will test the hypothesis that the high avidity cells detected at early times postinfection can give rise to low avidity ceils present at later times. In addition we will test the hypothesis that the level of peptide presented or the antigen presenting cell present at various times post infection controls the selective presence of high avidity anti-viral CD8+ T cells at early times (d3) postinfection. Given the emerging threat of the aerosolized delivery of bioterrorism agents (including viruses) on the battlefield, it is of the utmost importance that we increase our understanding of the immune response elicited following respiratory infection and mechanisms by which these pathogens can suppress that response. Results from these studies should provide information that will promote development of new vaccines that will provide optimal protection against respiratory pathogens.

我们工作的总体目的是确定调节肺部病毒感染响应于病毒感染的高流动性CD8+ T细胞激活和扩展的机制。保护性疫苗开发许多临床相关呼吸道病毒的困难表明，我们对促进肺部保护性免疫反应的参数的理解是不完整的。先前已经显示，识别低水平的抗原肽的高流行CD8+ T细胞是非常有效的免疫细胞，因为它们在感染后的早期识别靶细胞，而感染感染细胞的速度比低流行细胞更快。因此，高自然细胞的存在是最佳抗病毒反应的关键组成部分。我们已发表的数据表明，在感染呼吸道（D3）的早期（D3）使用帕托马病毒拟南芥病毒5或Poxvirus vaccinia病毒，CD8+ T细胞反应几乎完全是高发病率的。但是，在感染后的后期（D5），很容易检测到低自发性细胞，占总反应细胞的50-60％。对肺中存在的CD8+效应细胞的分析确定了该部位高发性细胞分泌IFN？或裂解细胞对刺激的裂解的能力的逐渐丧失。在高发性细胞中有选择性的功能丧失是一种新型的免疫抑制形式。在AIM 1中，我们将确定高发性细胞中功能不足的程度，以及低自发细胞是否表现出与非反应性诱导早期阶段一致的缺陷。随后的研究将研究负责功能变化的机制。最后，我们将检验以下假设，即在肺中存在的炎症环境中随着时间的流逝而变化，例如细胞因子和一氧化氮负责高发细胞中无响应性的诱导。 AIM 2中的研究分析了排水淋巴结中抗病毒CD8+ T细胞反应的产生。我们将测试以下假设：感染后早期检测到的高亲细胞可能会导致较晚的低潮天花板。此外，我们将检验以下假设：在感染后不同时间出现肽的水平或抗原存在的细胞，可在感染后早期（D3）选择性地存在高病毒抗病毒CD8+ T细胞。考虑到战场上生物恐怖剂（包括病毒）的雾化递送的新兴威胁，至关重要的是，我们会增加对呼吸感染后引起的免疫反应的理解和这些病原体可以抑制这种反应的机制。这些研究的结果应提供信息，以促进新疫苗的开发，从而为呼吸道病原体提供最佳保护。