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.

项目总结/摘要 流行性感冒（流感）感染是全球呼吸道疾病和死亡的主要原因， 在平均流感季节，有超过250，000例严重疾病和死亡。虽然流感疫苗 有效降低流感感染的发病率和死亡率，病毒的清除依赖于 强烈的免疫反应的发展，这也可能导致免疫病理学。重度流感 在人类患者中威胁生命的疾病伴随着侵袭性促炎性细胞因子， 反应和抗炎免疫力不足。这使得这项工作非常重要。的 由病毒特异性CD 8 + T细胞产生的免疫抑制细胞因子IL-10在限制免疫应答中是关键的。 然而，这种IL-10产生的时机是关键的。如果 如果它在早期产生，它会抑制效应免疫，但如果它在晚期产生， 将导致发病。了解CD 8 + T细胞如何调节IL-10的产生对于 了解如何控制流感引起的肺免疫病理学，然而，这还不清楚。基于 根据我们的研究结果，我们提出了ITK调节IL-10的发展的假设， 产生CD 8 + T细胞，从而控制甲型流感感染期间的免疫病理学。我们 我提出了两个具体目标的实验，以确定TCR/ITK信号转导在肿瘤发生中的作用。 甲型流感病毒感染过程中产生IL-10的CD 8 + T细胞的发育和免疫调节功能 感染这项工作是高度创新的，因为我们利用新颖独特的转基因小鼠模型，以及- 已经建立的方法和药物可追踪的目标，并有令人兴奋的初步数据， 将扩大到提供信息的信号通路，以更好地了解IL-10是如何 在病毒特异性T细胞中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， 向NIH提交R 01级别的更大规模的资助申请。 作为具体的研究项目之一，整合在正在进行的计划，建立该中心 肺生物学和疾病，这个项目调查的分子机制，通过IL-10- 产生CD 8 + T细胞调节流感诱导的肺免疫病理学与 计划使命。项目PI将成为该小组的主要成员，为建立一个 卓越生物医学研究中心（COBRE）在肺部生物学和疾病。该项目将 有助于肺免疫病理学、分子生物学和分子生物学的发展， 生物学和小鼠维护核心。