Cellular Immune Responses to Respiratory Infection

对呼吸道感染的细胞免疫反应

• 批准号: 7204197
• 负责人: Martha Ann Alexander-Miller
• 金额: $ 30.61万
• 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/7204197
• 关键词: Cellular; Immune; Responses; Respiratory; Infection

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.

我们工作的总体目标是确定调节高亲合力 CD8+ T 细胞响应肺部病毒感染的激活和扩增的机制。开发针对多种临床相关呼吸道病毒的保护性疫苗的困难表明，我们对促进肺部保护性免疫反应的参数的理解并不完整。先前已表明，识别低水平抗原肽的高亲和力 CD8+ T 细胞是非常有效的免疫细胞，因为它们在感染后较早识别靶细胞，并且比低亲和力细胞更快地裂解受感染的细胞。因此，高亲和力细胞的存在是最佳抗病毒反应的关键组成部分。我们发表的数据表明，在副粘病毒猿病毒 5 或痘苗病毒感染呼吸道后的早期（d3），CD8+ T 细胞反应几乎完全是高亲合力。然而，在感染后的晚些时候（d5），很容易检测到低亲和力细胞，占总反应细胞的 50-60%。对肺中存在的CD8+效应细胞的分析发现，该位点的高亲合力细胞分泌IFNα或响应刺激而裂解细胞的能力逐渐丧失。高亲合力细胞选择性丧失功能是一种新型的免疫抑制。在目标 1 中，我们将确定高亲和力细胞的功能缺陷程度，以及低亲和力细胞是否表现出与诱导无反应的早期阶段一致的缺陷。后续研究将调查导致功能变化的机制。最后，我们将检验肺部炎症环境随时间变化的假设，例如肺部炎症环境。细胞因子和一氧化氮负责诱导高亲合力细胞无反应。目标 2 中的研究分析了引流淋巴结中抗病毒 CD8+ T 细胞反应的产生。我们将检验以下假设：感染后早期检测到的高亲和力细胞可以产生稍后出现的低亲和力细胞。此外，我们将测试以下假设：感染后不同时间呈现的肽或抗原呈递细胞的水平控制着感染后早期（d3）高亲和力抗病毒CD8+ T细胞的选择性存在。鉴于战场上生物恐怖制剂（包括病毒）雾化输送的新威胁，我们最重要的是加深对呼吸道感染后引起的免疫反应以及这些病原体抑制这种反应的机制的了解。这些研究的结果应提供信息，促进新疫苗的开发，从而提供针对呼吸道病原体的最佳保护。