Cellular Immune Response to Respiratory Infection

描述（由申请人提供）：已知高亲和力CD 8 + T细胞是病毒清除的最有效介质。因此，了解病毒感染后如何控制亲合力对于设计最佳有效的治疗剂和疫苗至关重要。功能性亲合力定义为细胞对肽/MHC（pMHC）的敏感性。在应答性CD 8 + T细胞群内是涵盖广泛亲合力的效应子克隆。因此，产生混合的亲合力反应似乎是正常的。本申请中提出的研究建立在我们以前使用副粘病毒猿猴病毒5（SV 5）的发现基础上。该模型已被用于探索呼吸道感染后的抗病毒反应。我们已经进行了开创性的观察，呼吸道感染后，产生的初始CD 8+效应细胞表现出高亲合力表型。随着反应的进展，虽然高亲合力细胞继续扩增，但低亲合力也变得明显，包括约一半的抗病毒群体。本项目的总体目标是确定病毒感染后高亲和力细胞与低亲和力细胞出现动力学分离的机制。为此，在具体目标1中提出的研究将确定固有和诱导的亲合力对高与低亲合力T细胞生成的贡献。高亲合力细胞是初始应答者，而低亲合力细胞限于较晚时间的观察结果表明了两种假设：1）亲合力是由感染后早期与晚期存在的条件在应答细胞中诱导的，以及2）亲合力是初始T细胞的固有性质，并且高亲合力与低亲合力的那些细胞在早期与晚期被选择性激活。这将通过确定早期存在的细胞产生混合亲合力群体的能力来部分地测试。在后续研究中，将对naove样本池的固有亲合力进行操作，以确定早期与晚期对群体水平亲合力的影响。具体目标2中的研究目的是确定APC在控制亲合力中的作用。在高与低亲合力细胞存在下的动力学分离将表明在早期与晚期存在于淋巴结中的信号存在差异。在稍后的时间，这些信号将促进较早产生的高亲合力细胞中的亲合力下调，或者将导致具有固有较低亲合力的幼稚细胞的活化。目标二将检验APC是这一过程的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，在体内调节的亲合力和APC的作用，在确定不同的亲合力T细胞是如何在抗病毒反应的产生过程中扩大。此外，他们将提供新的信息，我们的理解不同的APC亚群的贡献，控制亲合力呼吸道感染。这些研究的结果可能会阐明新的干预机会，其中免疫反应是次优的，以及产生更多的保护性疫苗。已知高亲和力CD 8 + T细胞是病毒清除的最有效介质。从本申请中提出的新研究中获得的信息将通过提供病毒感染后亲合力如何在体内形成的模型来显著影响该领域。这些信息对于设计最佳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.