Impact of Resident Memory CD8 T Cells on Respiratory Virus Transmission

项目摘要/摘要 鼻腔接种和呼吸道病毒感染诱导抗原特异性B细胞和T细胞的形成 在粘膜组织中。由此产生的记忆T细胞识别跨病毒保守的内部表位 并且可以针对抗原性新颖的、可能大流行的变种提供保护。的一个子集 记忆性T细胞包括组织常驻记忆性T细胞(TRM)，它们可以提供快速免疫 病原体进入部位的反应。许多研究表明，使用直接鼻腔接种 呼吸道CD8TRM可介导对异亚型流感病毒株的保护作用。然而， CD8TRM限制呼吸道病毒自然传播的能力尚未确定。因为小鼠 适应的流感病毒不容易在小鼠和雪貂和豚鼠的免疫试剂之间传播 猪模型有限，研究传播背后的免疫学机制意义重大 受阻了。为了弥合这一认识上的差距，我们开发了一种使用仙台病毒的小鼠模型 在老鼠之间自然传播的副流感病毒。通过使用编码仙台的荧光素酶 病毒的传播动力学可以通过体内成像来评估。我们的初步数据表明 仙台病毒在呼吸道的特异性CD8 TRM限制了仙台病毒在免疫接触者中的传播。 我们试图进一步定义这种TRM介导的预防传播的机制 评估TRM在呼吸道不同解剖区段的相对贡献。因为 研究表明，肺和呼吸道TRM的下降对应于异型的丧失。 为了提高免疫力，我们将评估在各种疫苗接种策略下TRM介导的保护的持久性。 此外，我们将以细胞因子为重点，研究限制传播的TRM抗病毒机制。 和细胞溶解蛋白。了解呼吸道病毒传播的细胞免疫机制将影响 未来旨在预防呼吸道病毒暴发的疫苗开发。

PROJECT SUMMARY/ABSTRACT Intranasal vaccination and respiratory virus infection induces populations of antigen specific B cells and T cells in mucosal tissues. The resulting memory T cells recognize internal epitopes that are conserved across viral strains and can provide protection against antigenically novel, potentially pandemic variants. One subset of memory T cells includes tissue resident memory T cells (TRM) which are poised to provide rapid immune responses at the site of pathogen entry. Numerous studies using direct intranasal inoculation have demonstrated that CD8 TRM in the respiratory tract can mediate protection against heterosubtypic influenza strains. However, the ability of CD8 TRM to limit natural respiratory virus transmission has not been defined. Because murine adapted influenza viruses do not readily transmit between mice and immunological reagents for ferret and guinea pig models are limited, studying the immunological mechanisms behind transmission has been significantly hindered. To bridge this gap in knowledge, we developed a murine model using Sendai virus, a mouse parainfluenza virus which naturally transmits between mice. Through the use of a Luciferase encoding Sendai virus, transmission dynamics can be evaluated by in vivo imaging. Our preliminary data demonstrates that Sendai virus specific CD8 TRM in the respiratory tract limit transmission of Sendai virus to immunized contacts. We seek to further define the mechanisms underlying this TRM mediated protection against transmission by evaluating relative contributions of TRM in different anatomical compartments of the respiratory tract. Because studies have demonstrated that a decline in lung and airway TRM corresponds to a loss of heterosubtypic immunity, we will evaluate the durability of TRM mediated protection following various vaccination strategies. Furthermore, we will investigate the TRM antiviral mechanisms that limit transmission with a focus on cytokines and cytolytic proteins. Understanding cellular immune mechanisms in respiratory virus transmission will impact future vaccine development designed to prevent respiratory virus outbreaks.