Balancing protection versus immunopathology by RSV-specific memory CD8 T cells

摘要 呼吸道合胞病毒（RSV）是儿童、老年人和 免疫力低下的人。目前还没有获得许可的RSV疫苗。RSV特异性高滴度 抗体可以提供对严重的RSV诱导的疾病的保护;然而，即使是最高的抗体， 滴度不能保护一些个体免于RSV再感染和疾病。因此，保护的相关因素 对RSV免疫性仍不清楚。记忆性CD 8 T细胞可以提供针对广泛的免疫缺陷的保护性免疫。 一系列急性病毒感染，包括呼吸道病毒，如流感病毒和严重急性 呼吸综合征（SARS）人类冠状病毒。在大多数病毒感染中，记忆性CD 8 T细胞介导病毒感染。 清除，而不会对受感染的宿主造成实质性损害。因为很明显抗体本身 不足以提供对RSV感染的完全保护，我们假设诱导一种 在不存在RSV特异性记忆CD 4 T细胞的情况下，强的预先存在的RSV特异性记忆CD 8 T细胞应答 细胞和抗体将提供针对RSV感染的保护性免疫。为了测试我们的 假设我们修改了加速初免/加强方法以产生稳健的预先存在的记忆CD 8 T 特异于免疫显性M282-90表位的细胞群。我们的初步数据显示呼吸道合胞病毒- 特异性记忆性CD 8 T细胞可以显著抑制病毒复制，但出乎意料的是，这样做的代价是 在RSV攻击时引起致命的免疫病理学。重要的是，免疫病理学不是一个固有的 由于RSV特异性记忆性CD 8 T细胞能够介导保护作用， 针对用表达RSV衍生的病毒的重组流感病毒的致死性攻击的免疫病理学 M282-90表位。我们的数据显示，严格基于T细胞的RSV疫苗的设计可能具有严重的免疫缺陷。 后果因此，关于RSV特异性记忆性CD 8 T细胞是如何在体内表达的， 控制RSV感染的功能和导致免疫病理学发展的机制。的 本提案的目标是解决这些关键的知识差距，并提供机械的洞察，如果记忆 可以操纵CD 8 T细胞以赋予针对RSV感染的最佳保护性免疫。我们将实现 通过追求以下三个具体目标来实现这些目标：目标1。确定记忆CD 8 T的机制 RSV感染后细胞介导的免疫病理学。目标2.研究记忆的特征 在RSV攻击后增强免疫力并限制免疫病理学的CD 8 T细胞。目标3.定义 保护免受RSV感染的最佳相关性。从这些研究中获得的知识将提供 关于RSV保护性免疫相关性的重要信息，这些信息将极大地影响 设计和评价未来的RSV候选疫苗。 !

ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in children, the elderly and immunocompromised individuals. There is currently no licensed RSV vaccine. High titers of RSV-specific antibodies can provide protection against severe RSV-induced disease; however, even the highest antibody titers fail to protect some individuals against RSV reinfection and disease. Thus, the correlates of protective immunity against RSV remain unclear. Memory CD8 T cells can provide protective immunity against a wide range of acute viral infections, including respiratory viruses such as influenza virus and the severe acute respiratory syndrome (SARS) human coronavirus. In most virus infections, memory CD8 T cells mediate viral clearance without causing substantial damage to the infected host. Because it is clear that antibodies alone are not sufficient to provide complete protection against RSV infection, we hypothesized that induction of a strong pre-existing RSV-specific memory CD8 T cell response in the absence of RSV-specific memory CD4 T cells and antibodies would provide protective immunity against an RSV infection. In order to test our hypothesis we modified an accelerated prime/boost approach to generate robust pre-existing memory CD8 T cell populations specific to the immunodominant M282-90 epitope. Our preliminary data indicate that RSV- specific memory CD8 T cells can significantly inhibit viral replication, but unexpectedly do so at the cost of causing fatal immunopathology upon RSV challenge. Importantly, the immunopathology was not an inherent property of the T cells, as RSV-specific memory CD8 T cells were capable of mediating protection without immunopathology against a lethal challenge with a recombinant influenza virus expressing the RSV-derived M282-90 epitope. Our data reveal that the design of a strictly T cell-based RSV vaccine could have severe consequences. Thus, important knowledge gaps exist regarding how RSV-specific memory CD8 T cells function to control RSV infection and the mechanisms that result in the development of immunopathology. The goal of this proposal is to address these critical knowledge gaps and provide mechanistic insight into if memory CD8 T cells can be manipulated to confer optimal protective immunity against RSV infection. We will achieve these goals by pursuing the following three specific aims: Aim 1. Determine the mechanism of memory CD8 T cell-mediated immunopathology following RSV infection. Aim 2. Investigate the characteristics of memory CD8 T cells that enhance immunity and limit immunopathology after RSV challenge. Aim 3. Define the optimal correlates of protection against RSV infection. The knowledge gained from these studies will provide vital information regarding the correlates of protective immunity to RSV, information that will greatly impact the design and evaluation of future RSV vaccine candidates. !