Antigen Presentation After Influenza Virus Infection

流感病毒感染后抗原呈递

• 批准号: 8051692
• 负责人: Linda S Cauley
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051692
• 关键词: 3-Dimensional; Acute; Animals; Antibodies; Antigen Presentation; Antigens; CD8B1 gene; Cell Adhesion Molecules; Cells; Cellular Immunity; Cessation of life; Chronic; Confocal Microscopy; Cytotoxic T-Lymphocytes; Development; Doctor of Philosophy; Elderly; Engineering; Epitopes; Flow Cytometry; Foundations; Gene Targeting; Guanine Nucleotide Dissociation Inhibitors; Homing; Image; Immigration; Immune; Immunity; Immunocompromised Host; In Situ; Infection; Influenza; Laser Scanning Confocal Microscopy; Lung; Lung diseases; Maintenance; Measures; Memory; Modeling; Mucous Membrane; Mus; Parabiosis; Play; Process; Property; Receptor Signaling; Recombinants; Regulation; Residual state; Respiratory System; Respiratory tract structure; Role; Route; Shapes; Site; Structure of parenchyma of lung; Surface Antigens; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tissues; Vaccination; Viral; Viral Antigens; Viral Proteins; Virus; Virus Diseases; antigen processing; base; cell motility; influenzavirus; lymph nodes; migration; mucosal site; pathogen; prevent; receptor; response

DESCRIPTION (provided by applicant): Influenza is a highly contagious acute respiratory disease that is responsible for the deaths of large numbers of elderly and immunocompromised people each year. Cytotoxic T cells (CTL) play an important role in viral clearance and can provide short-term heterosubtypic immunity, indicating that they could be an effective supplement to antibody-based vaccination. The main advantage of targeting T cell responses is their ability to recognize epitopes in internal viral proteins that are conserved between different strains of virus, however the utility of the approach is limited by the short duration of the immunity that is established. In a recent study, we showed that processed T cell antigens persist in the draining lymph nodes of the respiratory tract for at least two months after infection, where they had a profound influence on local T cell migration and activation in the lungs. Based on these studies, we postulate that prolonged antigen presentation contributes to protective cellular immunity by retaining activated or partially-activated virus-specific CD8 T cells near the site of infection, where they can respond rapidly to reinfection. The studies to test this hypothesis will be divided into three parts: Aim 1. To determine which CD8 T cells respond to residual viral antigens in the draining lymph nodes. Aim 2. To identify mechanisms that control retention of virus-specific CD8 T cells in the lung tissues. Recombinant influenza viruses that differ only at a single T cell epitope, and gene targeted mice that lack specific adhesion molecules, will be used to determine how T cell surface antigens that are tightly regulated by T cell receptor (TcR)-signaling influence the retention of antigen-specific CD8 T cells near the site of infection. Aim 3. To determine how sustained antigen presentation impacts protective immunity and the development of a recall response during reinfection. Two serologically distinct viruses will be used to determine whether prolonged antigen presentation is essential for the maintenance of protective immunity. Primed mice will be joined to uninfected partners and separated after T cell equilibration, to compare the recall responses by migrating and non-migrating CD8 T cells in the presence and absence of residual viral antigens. Together, these studies will greatly increase our understanding of the mechanisms that regulate CD8 T cell responses in the respiratory tract and have important implications for vaccination in the lungs and other mucosal tissues.

描述（由申请人提供）：流感是一种高度传染性的急性呼吸道疾病，每年导致大量老年人和免疫功能低下的人死亡。细胞毒性T细胞（CTL）在病毒清除率中起着重要作用，可以提供短期异源性免疫，表明它们可能是基于抗体的疫苗接种的有效补充。靶向T细胞反应的主要优点是它们能够识别不同病毒菌株之间保守的内部病毒蛋白中表位的能力，但是该方法的效用受到建立免疫的短持续时间的限制。在最近的一项研究中，我们表明，在感染后至少两个月，在呼吸道的排水淋巴结中加工的T细胞抗原持续存在，它们对局部T细胞迁移和肺中的激活产生了深远的影响。基于这些研究，我们假设长时间的抗原表现通过保留感染部位附近的激活或部分激活的病毒特异性CD8 T细胞来促进保护性细胞免疫，从而可以迅速反应以重新感染。检验该假设的研究将分为三个部分：目标1。确定哪些CD8 T细胞对排水淋巴结中残留的病毒抗原反应。目的2。确定控制肺组织中病毒特异性CD8 T细胞保留的机制。仅在单个T细胞表位上有所不同的重组流感病毒以及缺乏特定粘附分子的基因靶向小鼠，将用于确定如何通过T细胞受体（TCR）签名紧密调节的T细胞表面抗原影响抗原特异性CD8 T细胞的保留，该保留影响抗原特异性CD8 T细胞附近的感染。目的3。确定持续的抗原表现如何影响保护性免疫以及在再感染过程中的召回反应的发展。将使用两种截然不同的病毒来确定长时间的抗原表现是否对于维持保护性免疫至关重要。启动小鼠将连接到未感染的伴侣并在T细胞平衡后分离，以在存在和不存在残留病毒抗原的情况下通过迁移和非迁移的CD8 T细胞来比较回忆反应。总之，这些研究将大大提高我们对调节呼吸道中CD8 T细胞反应的机制的理解，并对肺部和其他粘膜组织的疫苗接种具有重要意义。