T Cell Memory to Respiratory Viral Infections

描述（由申请人提供）：目前超过200种已知的病毒利用呼吸道作为进入宿主的入口。呼吸道病毒感染是全世界第三大死亡原因，也是世卫组织开发疫苗的一个重点。此外，高致病性病毒的出现，以及自然发生或修饰的病毒病原体可能用于生物恐怖活动，都突出了更好地了解控制肺部病毒保护性免疫机制的紧迫性。对于许多呼吸道病毒，CD8 T细胞已被证明在控制原发感染中发挥作用。此外，在传染性病毒被清除后，病毒特异性记忆CD8 T细胞可以在肺组织和气道中持续存在很长时间，这表明这些细胞在防止重复感染方面发挥了作用。CD8记忆问题的核心是定义控制它们有效产生和长期持续的调节机制，以及它们在回忆反应期间的再激活。了解CD8记忆是如何被调节的，对于设计更有效的疫苗来对抗感染和管理不良免疫反应至关重要。通过使用小鼠呼吸道痘苗病毒（VACV）感染模型，我们将验证保护性CD8 T细胞反应的产生是由肿瘤坏死因子受体（TNFR）家族成员OX40 （CD134）高度调节的观点。我们提供了支持这一假设的初步数据，我们将测试OX40在记忆性CD8 T细胞亚群上的组成性或诱导性表达是否控制抗原反应性和对VACV的保护能力。我们假设，在原发性感染解决后，OX40控制记忆CD8细胞在继发性应答中遇到抗原时的有效再激活和效应功能。我们还假设OX40决定了记忆CD8细胞的长期持久性。最后，我们将研究靶向OX40在未来是否有助于选择性地提高记忆性CD8 T细胞亚群对呼吸道VACV感染的保护能力。这些研究将提供关于共刺激分子在控制CD8 T细胞对呼吸道病毒感染反应中的重要性的宝贵数据，因此应该有助于制定策略来增强对致病性病毒的免疫反应，特别是正疱疹病毒家族的成员。

DESCRIPTION (provided by applicant): Currently over 200 known viruses utilize the respiratory tract as an entry point into the host. Respiratory viral infections are the third leading cause of death worldwide and are a WHO priority for vaccine development. Moreover, the emergence of highly pathogenic viruses, and the potential use of naturally occurring or modified viral pathogens for bioterrorist activities have highlighted the urgency to better understand the mechanisms that govern protective immunity against pulmonary viruses. For many respiratory viruses, CD8 T cells have been shown to play a role in control of primary infection. Moreover, virus-specific memory CD8 T cells can persist in the lung tissue and airways long after infectious virus has been cleared, suggesting a role for these cells in protection from repeated infections. Central to the question of CD8 memory is defining the regulatory mechanisms that govern their effective generation and long-term persistence, as well as their reactivation during recall responses. Understanding how CD8 memory is regulated is essential for designing more effective vaccines to combat infections and in the management of adverse immune reactions. By using a murine respiratory vaccinia virus (VACV) infection model we will test the idea that generation of protective CD8 T cell responses are highly regulated by the tumor-necrosis-factor receptor (TNFR) family member, OX40 (CD134). We present preliminary data supporting this hypothesis, and we will test whether, OX40, constitutively or inducibly expressed on memory CD8 T cell subsets control antigen reactivity and protective capacity to VACV. We hypothesize that after resolution of primary infection OX40 governs the effective reactivation and effector function of memory CD8 cells when they encounter antigen in secondary responses. We also hypothesize that OX40 then dictates long-term persistence of memory CD8 cells. Lastly, we will investigate whether targeting OX40 might be useful in the future to selectively improve the protective capacity of memory CD8 T cell subsets against respiratory VACV infection. These studies will provide invaluable data on the importance of costimulatory molecules in controlling CD8 T cell responses to respiratory viral infections and therefore should help in devising strategies to augmenting immune responses to pathogenic viruses, especially members of the orthopoxvirus family.