Cellular Immune Response to Respiratory Infection

描述（由申请人提供）：高亲和力的CD8+ T细胞是已知的最有效的病毒清除介质。因此，了解病毒感染后如何控制贪婪对于设计最有效的治疗方法和疫苗至关重要。功能性亲和度定义为细胞对多肽/MHC （pMHC）的敏感性。在应答的CD8+ T细胞群中是包含广泛活性的效应克隆。因此，产生一种混合的贪婪反应似乎是常态。本应用程序中提出的研究建立在我们以前使用类人猿副粘病毒5 （SV5）的研究结果的基础上。该模型已被用于研究呼吸道感染后的抗病毒反应。我们进行了开创性的观察，在呼吸道感染后，产生的初始CD8+效应细胞表现出高贪婪表型。随着反应的进展，虽然高贪婪细胞继续扩大，低贪婪也变得明显，包括大约一半的抗病毒人口。这里提出的项目的总体目标是确定在病毒感染后高与低贪婪细胞外观的动力学分离机制。为此，在特定目标1中提出的研究将确定固有和诱导贪婪度对高贪婪度和低贪婪度T细胞产生的贡献。观察到高贪婪细胞是最初的应答者，而低贪婪细胞仅限于较晚的时间，这提出了两种假设：1)贪婪在应答细胞中由感染后早期和晚期的条件诱导，2)贪婪是幼稚T细胞的固有特性，高贪婪和低贪婪的T细胞在早期和晚期被选择性激活。这将通过确定早期存在的细胞产生混合贪婪群体的能力来进行部分测试。在随后的研究中，将对中池的固有贪婪度进行操纵，以确定在早期和后期对种群水平贪婪度的影响。具体目标2的研究目标是确定APC在贪婪控制中的作用。在高和低贪婪细胞的存在下的动力学分离可能表明在早期和晚期淋巴结中的信号存在差异。在较晚的时间，这些信号会促进较早产生的高贪婪细胞的贪婪度下调，或者导致固有的低贪婪度的幼稚细胞的激活。目标二将检验APC是这一过程中关键组成部分的假设。总之，这些研究将揭示新的和重要的见解，在体内对贪婪度的调节和APC在决定不同贪婪度的T细胞如何在抗病毒反应的产生过程中扩增中的作用。此外，它们将为我们理解不同APC亚群对呼吸道感染后贪婪控制的贡献提供新的信息。这些研究的结果可能阐明在免疫反应不佳的地方进行干预的新机会，以及产生更具保护性的疫苗。众所周知，高亲和力的CD8+ T细胞是最有效的病毒清除介质。从本应用程序中提出的新研究中获得的信息将通过提供病毒感染后如何在体内形成贪婪的模型，对该领域产生重大影响。这一信息对于设计最有效的治疗方法和疫苗至关重要。

DESCRIPTION (provided by applicant): High avidity CD8+ T cells are known to be the most effective mediators of viral clearance. Thus understanding how avidity is controlled following viral infection is of critical importance for designing optimally effective therapeutics and vaccines. Functional avidity is defined as the sensitivity of the cell to peptide/MHC (pMHC). Within the responding CD8+ T cell population are effector clones that encompass a broad range of avidities. Thus generation of a mixed avidity response appears to be the norm. The studies proposed in this application build on our previous findings using the paramyxovirus simian virus 5 (SV5). This model has been utilized to probe the anti-viral response following respiratory tract infection. We have made the seminal observation that following respiratory infection, the initial CD8+ effector cells generated exhibit a high avidity phenotype. As the response progresses, while high avidity cells continue to expand, low avidity also become apparent comprising approximately half of the anti-viral population. The overall goal of the project proposed here is to determine the mechanism responsible for kinetic separation in the appearance of high versus low avidity cells following viral infection. To this end, the studies proposed in specific aim 1 will determine the contribution of inherent and induced avidity to the generation of high versus low avidity T cells. The observation that high avidity cells are the initial responders while low avidity cells are restricted to later times suggests two hypotheses: 1) Avidity is induced in the responding cells by the conditions present at early versus late times postinfection and 2) Avidity is an inherent property of naove T cells and those of high versus low avidity are selectively activated at early vs. late times. This will be tested in part by determining the ability of cells present at early times to give rise to a mixed avidity population. In subsequent studies the inherent avidity of the naove pool will be manipulated to determine the effects on avidity at the population level at early versus late times. The goal of the studies in specific aim 2 is to determine the role of APC in the control of avidity. The kinetic separation in the presence of high versus low avidity cells would suggest differences exist in signals present in the lymph node at early versus late times. At later times, these signals would promote avidity down-modulation in high avidity cells generated earlier or alternatively would cause the activation of naove cells with inherently lower avidity. Aim two will test the hypothesis that the APC is a key component in this process. Together these studies will reveal new and important insights into the in vivo regulation of avidity and the role of APC in determining how T cells that differ in avidity are expanded during generation of the anti-viral response. Further they will provide novel information with regard to our understanding of the contribution of distinct APC subsets to the control of avidity following respiratory infection. Results from these studies may elucidate novel opportunities for intervention where immune responses are suboptimal as well as for the generation of more protective vaccines. PUBLIC HEALTH RELEVANCE High avidity CD8+ T cells are known to be the most effective mediators of viral clearance. The information gained from the novel studies proposed in this application will significantly impact the field by providing a model for how avidity is shaped in vivo following viral infection. This information is of critical importance for designing optimally effective therapeutics and vaccines.