Long Term Effects of Influenza Virus on T Cell Migration

流感病毒对 T 细胞迁移的长期影响

• 批准号: 7098965
• 负责人: Linda S Cauley
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098965
• 关键词: antigens; cell migration; infection; influenza; lung; tissues

DESCRIPTION (provided by applicant): Influenza viruses are NIAID category C pathogens that represent a serious world-wide health problem for elderly and immune-compromised people every year. Human infections with a highly pathogenic strain of avian influenza virus have recently become the focus of intense international concern, since pandemic infections have the potential to cause colossal mortality rates in healthy adults. Cytotoxic T cells are an important defense mechanism that can promote viral clearance from the lungs. But the protection lasts only a few months even though large numbers of virus-specific CDS T cells persist in the organs of the infected animals several years. Increasing evidence suggests that T cell location during secondary viral challenge may be an important factor in protection, but the mechanisms that control T cell retention near the site of viral infection are poorly understood. Our preliminary data show that processed viral antigens are presented in v/vofor several weeks (and maybe months) after pulmonary influenza virus infection. Based on these data we postulate that chronic stimulation with antigen helps maintain activated CDS T cells near the site of viral infection. Two specific aims will be used to test this hypothesis. AIM 1. To investigate how residual viral antigens influence local CDS T cell migration in the lungs and MLN after pulmonary influenza virus infection. Transfer studies will determine the full duration and anatomical location of antigen presentation in influenza infected mice. In addition, in situ class I MHC tetramer analysis will be used to localize antigen-specific CDS T cells in the tissues and visualize their interactions with other accessory cells and/or adhesion molecules that may impede their migration. AIM 2. To investigate whether CD11c+ antigen presenting cells (APCs) are required for presentation of residual viral antigens to T cells after influenza virus infection. Mice that express the human diphtheria toxin receptor under the control of the CD11c promoter (CD11c-DTR) will be used to make chimeric mice with ablation-sensitive CD11 c+ APCs. These mice will be used to determine whether T cell activation in the lungs is prevented when antigen-bearing APCs are depleted in vivo.

描述（由申请人提供）：流感病毒是NIAID类别C病原体，代表了每年对老年人和免疫受损的人的严重健康问题。由于大流行感染有可能导致健康成年人的巨大死亡率，因此对禽流感病毒高度致病性菌株的人类感染最近已成为强烈关注的焦点。细胞毒性T细胞是一种重要的防御机制，可以促进肺部病毒清除率。但是，即使在受感染动物的器官中持续存在大量病毒特异性的CD T细胞，该保护也只能持续几个月。越来越多的证据表明，在继发病毒挑战期间的T细胞位置可能是保护的重要因素，但是控制病毒感染部位附近T细胞保留的机制知之甚少。我们的初步数据表明，肺流感病毒感染后几周（甚至几个月）在V/VOFOR中介绍了加工的病毒抗原。基于这些数据，我们假设用抗原慢性刺激有助于维持病毒感染部位附近活化的CDS T细胞。将使用两个具体目标来检验这一假设。目的1。研究残留病毒抗原如何影响肺流感病毒感染后肺和MLN的局部CD细胞迁移。转移研究将确定抗原感染小鼠中抗原表现的全持续时间和解剖位置。此外，原位I类MHC四聚体分析将用于将抗原特异性CDS T细胞定位在组织中，并可视化它们与其他辅助细胞和/或可能阻碍其迁移的粘附分子的相互作用。目的2。要研究CD11C+抗原呈递细胞（APC）是否需要在流感病毒感染后将残留的病毒抗原向T细胞呈递。在CD11C启动子（CD11C-DTR）控制下表达人白喉毒素受体的小鼠将用于使具有消融敏感CD11 C+ APC的嵌合小鼠。这些小鼠将用于确定当含有抗原的APC在体内耗尽时，是否可以预防肺中的T细胞激活。