TCR signaling in IL-10 production by CD8+ T cells during influenza-induced lung immunopathology

流感诱导的肺部免疫病理过程中 CD8 T 细胞产生 IL-10 的 TCR 信号转导

• 批准号: 10078640
• 负责人: Weishan Huang
• 金额: $ 23.55万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-02 至 2021-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078640
• 关键词: Anti-Inflammatory Agents; Antibodies; Antigens; Applications Grants; Bacterial Infections; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cause of Death; Cells; Centers of Research Excellence; Cessation of life; Data; Development; Disease; Grant; Human; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory Response; Influenza; Influenza A virus; Interleukin-10; Interleukin-2; Kinetics; Knowledge; Lead; Life; Lung; Lung diseases; Maintenance; Mediating; Mission; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Patients; Pharmacologic Substance; Phosphotransferases; Production; Protein Tyrosine Kinase; Receptor Signaling; Recurrence; Regulation; Research; Research Project Grants; Role; Seasons; Signal Pathway; Signal Transduction; T cell response; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Transgenic Mice; United States National Institutes of Health; Vaccines; Viral; Viral Antigens; Virus; Work; adaptive immune response; base; cytokine; cytotoxic; cytotoxic CD8 T cells; emt protein-tyrosine kinase; experimental study; flu; genetic approach; immunopathology; immunoregulation; in vivo; influenza infection; influenza virus vaccine; innovation; member; mortality; mouse model; novel; pandemic influenza; programs; response

Project Summary / Abstract Influenza (flu) infection is a leading cause of respiratory disease and death worldwide, causing 3-5 million cases of severe illness and more than 250,000 deaths during an average flu season. While flu vaccines are effective at reducing the morbidity and mortality of flu infections, clearance of virus relies on the development of a strong immune response, which can also cause immunopathology. Severe influenza diseases that are life-threatening in human patients are accompanied by an aggressive pro-inflammatory response and an insufficient anti-inflammatory immunity. This makes this work highly significant. The production of the immunosuppressive cytokine IL-10 by viral specific CD8+ T cells is critical in limiting the immunopathology during flu infection, however the timing of this IL-10 production is critical. If it is produced to early, it suppresses the effector immunity, but if it is produced to late, immunopathology and morbidity will result. Understanding how IL-10 production by CD8+ T cells is regulated is critical for understanding how to control flu-induced lung immunopathology, however, this is not yet clear. Based on our results, we have developed the hypothesis that ITK regulates the development of IL-10- producing CD8+ T cells, thus controlling immunopathology during influenza A infection. We propose experiments in two specific aims to determine the role of the TCR/ITK signaling in the development and immunomodulatory function of IL-10-producing CD8+ T cells during Influenza A infection. This work is highly innovative as we utilize novel and unique transgenic mouse models, well- established approaches and a pharmaceutically traceable target, and have exciting preliminary data that will be expanded to provide information on a signaling pathway for better understanding of how IL-10 is regulated in virus-specific T cells to control virus-induced immunopathology, morbidity and mortality. Completion of the proposed research will generate essential data and information set to support submission of a larger scale grant application in the R01 level to the NIH. As one of the specific research projects integrated in the ongoing program to establish the Center for Lung Biology and Disease, this project investigating the molecular mechanisms through which IL-10- poducing CD8+ T cells modulate flu-induced lung immunopathology is in perfect alignment with the program mission. The project PI will be a key member of the group to contribute to the establishment of a Center of Biomedical Research Excellence (COBRE) in Lung Biology and Disease. This project will contribute to the development and benefit from the usages of Pulmonary Immunopathology, Molecular Biology, and Mouse Maintenance cores.

项目概要/摘要 流感 (flu) 感染是全球呼吸系统疾病和死亡的主要原因，导致 3-500 万人死亡 平均流感季节期间会出现严重疾病病例和超过 250,000 人死亡。虽然流感疫苗 能有效降低流感感染的发病率和死亡率，病毒的清除依赖于 产生强烈的免疫反应，这也可能引起免疫病理学。严重流感 危及人类患者生命的疾病都伴随着侵袭性的促炎症反应 反应和抗炎免疫力不足。这使得这项工作非常有意义。这 病毒特异性 CD8+ T 细胞产生免疫抑制细胞因子 IL-10 对于限制 流感感染期间的免疫病理学，然而 IL-10 产生的时间至关重要。如果是的话 产生得太早，它会抑制效应免疫，但如果产生得太晚，免疫病理学和 就会导致发病。了解 CD8+ T 细胞产生 IL-10 的调控机制对于 了解如何控制流感引起的肺部免疫病理学，然而，这尚不清楚。基于 根据我们的结果，我们提出了这样的假设：ITK 调节 IL-10-的发育 产生 CD8+ T 细胞，从而控制甲型流感感染期间的免疫病理学。我们 提出两个具体目标的实验，以确定 TCR/ITK 信号传导在 甲型流感期间产生 IL-10 的 CD8+ T 细胞的发育和免疫调节功能 感染。这项工作具有高度创新性，因为我们利用新颖且独特的转基因小鼠模型， 已建立的方法和药物可追溯的目标，并拥有令人兴奋的初步数据 将进行扩展以提供有关信号传导途径的信息，以便更好地了解 IL-10 的作用 在病毒特异性 T 细胞中进行调节，以控制病毒诱导的免疫病理学、发病率和死亡率。 完成拟议的研究将产生必要的数据和信息集来支持 向 NIH 提交 R01 级别的更大规模资助申请。 作为正在进行的建立该中心计划中纳入的具体研究项目之一 对于肺生物学和疾病，该项目研究了 IL-10- 的分子机制 产生 CD8+ T 细胞调节流感诱导的肺部免疫病理学与 计划任务。项目PI将作为小组的关键成员，为建立一个 肺生物学和疾病生物医学卓越研究中心 (COBRE)。该项目将 为肺免疫病理学、分子生物学的发展做出贡献并从中受益 生物学和小鼠维护核心。