Type I Interferon-Regulated T Helper Development

描述（由申请人提供）：CD 4 + T辅助（Th）细胞通过分泌特定细胞因子亚群调节适应性细胞介导的免疫的多个方面。虽然它们的活性在对病原生物体的反应中至关重要，但CD 4 + T细胞也可以介导与各种炎症过程相关的病理。具体而言，Th 2细胞是通过分泌效应细胞因子IL-4、IL-5和IL-13协调哮喘炎症的关键细胞亚群。IL-4通过诱导关键转录因子GATA 3驱动CD 4 + T细胞中的Th 2发育。与先天性细胞因子IL-1/2和IFN-3不同，我们最近证明I型干扰素（IFN-1/2）抑制IL-4驱动的Th 2细胞的发育和表型稳定性。我们进一步证明，IFN-1阻断这一发展途径，通过抑制GATA 3的表达。因此，我们推测IFN-1/2在体内可以阻断哮喘Th 2细胞分泌细胞因子，逆转哮喘的致病作用。我们将解决这一假设与以下目标：目标1：表征的表型和功能的Th 2细胞进行重定向与IFN-1/2。目的2：探讨IFN-1/2阻断GATA 3表达的分子机制。目的3：观察IFN-1/2对哮喘患者Th 2细胞表型稳定性和细胞因子分泌的影响。这些研究的结果将为使用IFN-1/2治疗哮喘的新方法奠定基础。 公共卫生相关性：哮喘是一种使人衰弱的肺部炎症性疾病，影响着全世界数百万人。虽然有各种疗法可以提供暂时的缓解，并且在某些情况下可以立即使用吸入器进行挽救生命的干预，但还没有开发出阻止疾病慢性进展和维持的治疗方法。哮喘是一种免疫介导的疾病，由CD 4 + T细胞不适当地活化为环境中通常无害的分子引起。这些活化的T细胞分泌可溶性细胞因子，如白细胞介素-4，其激活肺中的炎症过程的级联反应。因此，CD 4 + T细胞是逆转哮喘发病机制的主要靶点。在我们的研究中，我们发现一种独特的细胞因子，I型干扰素（IFN- a/B），有效地阻断这些炎性T细胞的发展并抑制它们分泌细胞因子的能力。基于这一观察结果，本提案试图理解IFN-α/B逆转这些致病性T细胞的机制，并将确定IFN-α/B是否可以阻断从哮喘患者分离的这些炎性T细胞的细胞因子分泌。这些研究将为更有效和持久的过敏和哮喘治疗奠定基础。

DESCRIPTION (provided by applicant): CD4+ T helper (Th) cells regulate multiple aspects of adaptive cell mediated immunity through the secretion of specific subsets of cytokines. While their activities are critical in responses to pathogenic organisms, CD4+ T cells can also mediate pathologies associated with various inflammatory processes. Specifically, Th2 cells are the key subset of cells that orchestrate the inflammation of asthma through the secretion of the effector cytokines IL-4, IL-5, and IL-13. IL-4 drives Th2 development in CD4+ T cells through the induction of a key transcription factor GATA3. Unlike the innate cytokines IL-12 and IFN-3, we have recently demonstrated that type I interferon (IFN-1/2) inhibits the development and phenotype stability of IL-4-driven Th2 cells. We further demonstrate that IFN-1 blocks this developmental pathway by repressing GATA3 expression. Based on our findings, we propose that IFN-1/2 could block cytokine secretion of asthmatic Th2 cells and reverse the pathogenic effects in vivo. We will address this hypothesis with the following aims: Aim 1: Characterize the phenotype and function of Th2 cells undergoing redirection with IFN-1/2. Aim 2: Determine the molecular mechanism by which IFN-1/2 blocks GATA3 expression. Aim 3: Determine the ability of IFN-1/2 to inhibit phenotype stability and cytokine secretion from Th2 cells isolated from asthmatic patients. The results from these studies will form the basis for new therapeutic approaches to treat asthma involving IFN-1/2. PUBLIC HEALTH RELEVANCE: Asthma is a debilitating inflammatory disease of the lungs that affects millions of people worldwide. While various therapies are in place to provide temporary relief, and in some cases immediate life- saving intervention with inhalers, no treatment has been developed that blocks the chronic progression and maintenance of the disease. Asthma is an immune-mediated disorder caused by the inappropriate activation of CD4+ T cells to normally innocuous molecules in the environment. These activated T cells secrete soluble cytokines, such as interleukin-4, that activate a cascade of inflammatory processes in the lung. Thus, CD4+ T cells represent the primary target for reversing the pathogenesis of asthma. In our studies, we have found that a unique cytokine, type I interferon (IFN- a/b), potently blocks the development of these inflammatory T cells and inhibits their ability to secrete cytokines. Based on this observation, this proposal seeks to understand the mechanism by which IFN-a/b reverses these pathogenic T cells and will determine whether IFN-a/b can block cytokine secretion from these inflammatory T cells isolated from asthma sufferers. These studies will lay the groundwork for more effective and long-lasting treatment for allergy and asthma.