Cellular Immune Responses to Respiratory Infection

我们工作的总体目标是确定在肺部病毒感染反应中调节高亲和性CD8+ T细胞激活和扩增的机制。开发针对许多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是不完整的。先前的研究表明，识别低水平抗原肽的高亲和度CD8+ T细胞是非常有效的免疫细胞，因为它们在感染后更早地识别靶细胞，并且比低亲和度细胞更快地溶解感染细胞。因此，高贪婪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类人猿病毒5或痘病毒牛痘病毒后的早期（d3）， CD8+ T细胞的反应几乎完全是高的。然而，在感染后的后期（d5），很容易检测到低贪婪细胞，占总应答细胞的50-60%。对肺中CD8+效应细胞的分析发现，该部位的高活性细胞分泌IFN的能力逐渐丧失。或对刺激作出反应而使细胞溶解。高贪婪细胞选择性功能丧失是一种新的免疫抑制形式。在目标1中，我们将确定高贪婪细胞功能缺陷的程度，以及低贪婪细胞是否表现出与诱导无反应的早期阶段一致的缺陷。后续的研究将探讨导致功能改变的机制。最后，我们将验证一个假设，即随着时间的推移，肺部炎症环境的变化，例如细胞因子和一氧化氮，是导致高贪婪细胞无反应性的原因。目的2的研究分析了引流淋巴结中抗病毒CD8+ T细胞反应的产生。我们将验证在感染后早期检测到的高贪婪细胞可以引起在后期出现的低贪婪细胞的假设。此外，我们将检验在感染后不同时间呈递的肽或抗原呈递细胞的水平控制在感染后早期（d3）高亲和力抗病毒CD8+ T细胞的选择性存在的假设。鉴于战场上生物恐怖主义制剂（包括病毒）的雾化递送新出现的威胁，我们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至关重要。这些研究的结果应提供信息，以促进开发能够提供最佳保护以抵御呼吸道病原体的新疫苗。

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.