Regulation of IL10 production in CD8+ T cells during Flu infection by tyrosine kinase Itk

流感感染期间酪氨酸激酶 Itk 对 CD8 T 细胞 IL10 产生的调节

基本信息

批准号：
10165477
负责人：
Avery August
金额：
$ 38.92万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-18 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165477
关键词：
Antibodies Bacterial Infections CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cause of Death Cells Cessation of life Coronavirus Infections Cytotoxic T-Lymphocytes Data Development IL2 gene IRF4 gene Immune response In Vitro Infection Influenza Influenza A virus Interleukin-10 Interleukin-12 Interleukin-2 Kinetics Lead Morbidity - disease rate Neutrophilia Pathway interactions Phosphotransferases Process Production Protein Tyrosine Kinase Recurrence Regulation Respiratory Syncytial Virus Infections Respiratory Tract Infections Role Signal Pathway T cell response T-Cell Receptor T-Lymphocyte Testing Transgenic Mice Viral Virus Virus Diseases Work adaptive immune response base cytokine cytotoxic emt protein-tyrosine kinase experimental study flu genetic approach immunopathology in vivo influenza infection influenza virus vaccine influenzavirus innovation mortality novel pandemic influenza response transcription factor

项目摘要

Project Summary / Abstract Influenza (flu) infection is the leading cause of respiratory infection, causing 3-5 million cases of severe illness and greater than 500,000 deaths worldwide. While flu vaccines are effective at reducing the mortality and morbidity of flu infections, clearance of virus relies on the development of a strong immune response, which can also cause immunopathology. This makes this work highly significant. The production of the immunosuppressive cytokine IL10 by viral specific CD8+ T cells is critical in limiting the immunopathology during flu infection, however the timing of this IL10 production is critical, too early and it suppresses the immune response, too late and immunopathology and morbidity results. Understanding how IL10 production by CD8+ T cells is regulated is critical for understanding how to control this immunopathology, however, this is incompletely understood. Based on our results, we have developed the hypothesis that Itk regulates the development of IL10-producing CD8+ T cells, thus controlling immunopathology during influenza A infection. We propose experiments in three specific aims that will determine the role of Itk in the development of IL10-producing CD8+ T cells and immunopathology during Influenza A infection, in the suppressive function of IL10-producing CD8+ T cells, and the mechanism by which Itk regulates IL10 production in CD8+ T cells. This work is extremely innovative as we utilize novel and unique transgenic mice and approaches, and have exciting preliminary data that when fleshed out, will provide information on how IL10 is regulated in virus specific T cells to control virus-induced immunopathology, morbidity and mortality.

项目摘要 /摘要流感（流感）感染是呼吸道感染的主要原因，导致3-5万例严重疾病全世界大于500,000人死亡。流感疫苗可有效降低死亡率和流感感染的发病率，病毒的清除依赖于强烈的免疫反应的发展，这也可能引起免疫病理学。这使得这项工作非常重要。生产病毒特异性CD8+ T细胞免疫抑制细胞因子IL10对于限制免疫病理至关重要在流感感染期间，这种IL10产生的时机至关重要，太早了，它抑制了免疫反应，太晚，免疫病理学和发病率。了解IL10如何通过调节CD8+ T细胞对于理解如何控制这种免疫病理学至关重要，但是，这是不完全理解。根据我们的结果，我们提出了这样的假设，即ITK调节了产生IL10的CD8+ T细胞的开发，从而控制流感期间的免疫病理学感染。我们提出了三个特定目标的实验，这些实验将决定ITK在开发中的作用在抑制功能中，在流感A感染过程中产生IL10的CD8+ T细胞和免疫病理学产生IL10的CD8+ T细胞以及ITK调节CD8+ T细胞中IL10产生的机制。这项工作非常创新，因为我们利用了新颖和独特的转基因小鼠和方法，并且具有令人兴奋的初步数据，当充实时，将提供有关如何在病毒中调节IL10的信息特定的T细胞控制病毒诱导的免疫病理学，发病率和死亡率。