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

• 批准号: 10413052
• 负责人: Avery August
• 金额: $ 38.92万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413052
• 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

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.

项目总结/摘要 流行性感冒（流感）感染是呼吸道感染的主要原因，造成3-5万例重症病例 全世界有超过五十万人死亡虽然流感疫苗能有效降低死亡率， 在流感感染的发病率，病毒的清除依赖于强大的免疫反应的发展， 也会引起免疫病理学这使得这项工作非常重要。的生产 通过病毒特异性CD 8 + T细胞的免疫抑制细胞因子IL 10在限制免疫病理学方面是关键的 然而，在流感感染期间，这种IL 10产生的时机是至关重要的，过早，它抑制了流感病毒的产生。 免疫反应，太晚和免疫病理学和发病率的结果。了解IL 10生产如何通过 CD 8 + T细胞的调节对于理解如何控制这种免疫病理学至关重要，然而，这是 不完全理解。基于我们的研究结果，我们提出了Itk调节 产生IL 10的CD 8 + T细胞的发育，从而控制甲型流感期间的免疫病理学 感染我们提出了三个具体目标的实验，这些目标将确定Itk在发展中的作用。 IL-10产生的CD 8 + T细胞和免疫病理学在甲型流感感染期间，在抑制功能 IL-10产生的CD 8 + T细胞，以及Itk调节CD 8 + T细胞中IL-10产生的机制。 这项工作是非常创新的，因为我们利用新颖独特的转基因小鼠和方法， 令人兴奋的初步数据，当充实出来时，将提供关于IL 10如何在病毒中调节的信息。 特异性T细胞来控制病毒诱导的免疫病理学、发病率和死亡率。