Innate Regulation of CD8+ T Cell Effector Activites

CD8 T 细胞效应器活性的先天调节

• 批准号: 7746104
• 负责人: RICHARD I ENELOW
• 金额: $ 39.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746104
• 关键词: Alveolar; Antigen-Presenting Cells; Antigens; Antiviral Agents; Binding; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Death; Cells; Clinical; Competence; Consensus; Coronavirus; Data; Dendritic Cells; Dependence; Development; Epigenetic Process; Event; Gene Expression; Genes; Genetic Transcription; Harvest; Human; Immune; Immune response; Infection; Influenza; Injury; Interferon Type I; Interferon Type II; Interferons; Interleukin-10; Kinetics; Knockout Mice; Ligands; Light; Location; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Mediastinal lymph node group; Mediating; Memory; Modification; Mus; Natural Killer Cells; Nature; Nuclear Extract; Oligonucleotides; Outcome; Pneumonia; Population; Predisposition; Process; Production; Property; Publishing; Receptor Signaling; Regulation; Relative (related person); Role; Sampling; Signal Transduction; Site; Source; Structure of parenchyma of lung; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Transcriptional Activation; Viral; Viral Antigens; Virus; Virus Diseases; chromatin immunoprecipitation; comparative; cytotoxic; design; immunopathology; in vivo; lung injury; lymph nodes; programs; promoter; receptor; receptor expression; reconstitution; respiratory infection virus; respiratory virus; response; type I interferon receptor

Infection with respiratory viruses, such as with influenza, coronavirus, and others, results in considerable pulmonary immunopathology, a large component of which results from the host specific immune responses,. Type 1 interferons (IFN-a(3) represent an important component of the innate immune response to most virus infections, and most strains of virus, including the highly pathogenic strains of influenza, have evolved mechanisms to suppress or evade these defenses. In addition to the direct inhibition of viral replication, type 1 interferons possess a variety of other immunomodulatory properties. Recently, however, it has become apparent that lung injury which occurs in the context of the T cell response to experimental influenza infection is considerably more severe in the absence of the IFN-a(3 receptor, and this is not a result of enhanced viral replication. Our data indicate that expression of the inhibitory NKG2A receptor on CD8+ T cells, which is usually induced during the course of viral clearance, is not significantly induced in the absence of the IFN-a3-receptor. Furthermore, the activation threshold of CD8+ T cells is increased by NKG2A activity, and when NKG2A binding to its cognate receptor is blocked, enhanced T cell effector activity is observed. Examination of the requirements for induction of inhibitory NKG2A expression by CD8+ T cells in influenza infection suggests that initial antigen recognition in the presence of IFN-a(3 in the regional lymph node is probably required, though expression is not observed until the cells reach the effector site in the periphery (i.e. the lung parenchyma). In order to understand the role of type 1 interferons on the inhibition of pulmonary immunopathology in respiratory virus infection, we will test the hypothesis that initial antigen engagement in the presence of type 1 interferon results in "priming" for CD8+ T cell inhibitory NKG2A expression, but that actual receptor expression on CD8+ T cells requires antigen recognition in the lung parenchyma, probably on professional antigen-presenting cells such as dendritic cells. Specifically we propose to analyze the direct and indirect effects of type I interferon on regulation of CD8+ T cell NKG2A expression and immunopathologic potential, and to understand the mechanisms of regulation of CD8+ T cell NKG2A expression by IFN-a(3. This will shed important light into the mechanisms of fine-tuning of the antiviral adaptive immune responses to optimize virus clearance and minimize tissue damage which may occur in the process.

感染呼吸道病毒，如流感、冠状病毒等，会导致相当大的 肺免疫病理学，其中很大一部分是由宿主特异性免疫应答引起的。 1型干扰素（IFN-α）是对大多数病毒的先天免疫应答的重要组成部分 大多数病毒株，包括高致病性流感病毒株， 抑制或逃避这些防御的机制。除了直接抑制病毒复制外， 1干扰素具有多种其他免疫调节特性。然而，最近， 显然，在T细胞对实验性流感的反应中发生的肺损伤 在缺乏IFN-α β受体的情况下，感染严重得多，这不是 增强病毒复制。我们的数据表明，CD 8 + T细胞上抑制性NKG 2A受体的表达 通常在病毒清除过程中诱导的细胞， IFN-a3受体。此外，NKG 2A增加了CD 8 + T细胞的活化阈值 活性，并且当NKG 2A与其同源受体的结合被阻断时，增强的T细胞效应子活性被阻断。 观察检查受试者中CD 8 + T细胞诱导抑制性NKG 2A表达的要求 流感感染表明在局部淋巴中存在IFN-α β时初始抗原识别 淋巴结可能是必需的，尽管直到细胞到达淋巴结中的效应位点才观察到表达。 外周（即肺实质）。为了了解1型干扰素在抑制 呼吸道病毒感染的肺免疫病理学，我们将测试的假设， 在1型干扰素存在下的接合导致CD 8 + T细胞抑制性NKG 2A的“引发” 表达，但CD 8 + T细胞上的实际受体表达需要肺中的抗原识别 软组织，可能位于专职抗原递呈细胞（例如树突状细胞）上。另外还 拟分析I型干扰素对CD 8 + T细胞NKG 2A调节的直接和间接作用 表达和免疫病理学潜力，并了解CD 8 + T细胞的调节机制 通过IFN-α表达NKG 2A（3.这将揭示重要的机制，微调的 抗病毒适应性免疫应答，以优化病毒清除并使组织损伤最小化， 发生在这个过程中。