Cellular Immune Responses to Respiratory Infection

我们工作的总体目标是确定调节高亲和力CD 8 + T细胞响应于肺部病毒感染的活化和扩增的机制。针对许多临床相关呼吸道病毒的保护性疫苗开发的困难表明，我们对促进肺部保护性免疫应答的参数的理解是不完整的。先前已经表明，识别低水平抗原肽的高亲合力CD 8 + T细胞是非常有效的免疫细胞，因为它们在感染后较早的时间识别靶细胞，并且比低亲合力细胞更快地裂解感染的细胞。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，在呼吸道感染副粘病毒猿猴病毒5或痘病毒牛痘病毒后的早期（d3），CD 8 + T细胞应答几乎完全是高亲和力。然而，在感染后的稍后时间（d5），容易检测到低亲合力细胞，其占总应答细胞的50-60%。对肺中存在的CD 8+效应细胞进行分析，发现该部位高亲和力细胞分泌IFN？的能力进行性丧失，或响应刺激而裂解细胞。在高亲合力细胞中选择性地丧失功能是一种新的免疫抑制形式。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性的早期阶段一致的缺陷。随后的研究将调查负责功能变化的机制。最后，我们将测试的假设，即随着时间的推移，在肺部的炎症环境，如细胞因子和一氧化氮的变化，是负责诱导高亲和力细胞的无反应性。目的2中的研究分析了引流淋巴结中抗病毒CD 8 + T细胞应答的产生。我们将检验这样一个假设，即在感染后早期检测到的高亲合力细胞可以在后期产生低亲合力细胞。此外，我们将检验以下假设：在感染后不同时间呈递的肽或抗原呈递细胞的水平控制感染后早期（d3）高亲合力抗病毒CD 8 + T细胞的选择性存在。考虑到战场上生物恐怖主义制剂（包括病毒）的雾化传播的新威胁，我们必须进一步了解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。这些研究的结果应该提供信息，将促进新疫苗的开发，将提供最佳的保护，对呼吸道病原体。

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.