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

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300-500万例严重疾病 全球死亡人数超过50万人。虽然流感疫苗在降低死亡率和 流感感染的发病率、病毒的清除有赖于发展出强大的免疫反应，这 也会引起免疫病理。这使得这项工作具有非常重要的意义。这部电影的制作 病毒特异性CD8+T细胞产生的免疫抑制细胞因子IL10在限制免疫病理过程中起关键作用 然而，在流感感染期间，IL10产生的时机至关重要，为时过早，它抑制了 免疫反应、为时已晚以及免疫病理学和发病率的结果。了解IL10如何通过以下方式产生 CD8+T细胞的调节对于理解如何控制这种免疫病理至关重要，然而，这是 不完全理解。基于我们的结果，我们提出了ITK调节 产生IL10的CD8+T细胞的发育，从而控制甲型流感期间的免疫病理 感染。我们提出了三个特定目标的实验，这将决定ITK在发展中的作用 甲型流感感染过程中产生IL-10的CD8+T细胞与免疫病理的关系 以及ITK调节CD8+T细胞产生IL10的机制。 这项工作极具创新性，因为我们利用了新的和独特的转基因小鼠和方法，并具有 令人兴奋的初步数据，当充实时，将提供有关IL10如何在病毒中调节的信息 控制病毒诱导的免疫病理、发病率和死亡率的特定T细胞。

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.