Type I Interferon-Regulated T Helper Development

描述(由申请人提供)：CD4T辅助(Th)细胞通过分泌特定的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CD4T细胞的活性在对病原体的反应中至关重要，但它也可以介导与各种炎症过程相关的病理过程。具体地说，Th2细胞是通过分泌效应细胞因子IL-4、IL-5和IL-13来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GATA3在CD4T细胞中驱动Th2的发育。与固有的细胞因子IL-12和干扰素-3不同，我们最近证明了I型干扰素(干扰素-1/2)抑制了IL-4驱动的Th2细胞的发育和表型稳定性。我们进一步证明，干扰素-1通过抑制GATA3的表达来阻断这一发育途径。根据我们的研究结果，我们认为干扰素-1/2可以在体内阻断哮喘Th2细胞分泌细胞因子，逆转哮喘的致病作用。我们将从以下几个方面探讨这一假说：目的1：研究干扰素-1/2重定向Th2细胞的表型和功能。目的2：确定干扰素-1/2阻断GATA3表达的分子机制。目的：检测干扰素-1/2对哮喘患者Th2细胞表型稳定性和细胞因子分泌的抑制作用。这些研究的结果将为治疗涉及干扰素-1/2的哮喘的新的治疗方法奠定基础。 与公共卫生相关：哮喘是一种使人衰弱的肺部炎症性疾病，影响全球数百万人。虽然已经有各种疗法来提供暂时缓解，在某些情况下用吸入器立即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CD4T细胞不适当地激活环境中正常无害的分子而引起。这些被激活的T细胞分泌可溶的细胞因子，如白介素4，激活肺部的一连串炎症过程。因此，CD4T细胞是逆转哮喘发病机制的主要靶点。在我们的研究中，我们发现了一种独特的细胞因子，I型干扰素(IFN-a/b)，它能有效地阻止这些炎性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，本建议试图了解干扰素-a/b逆转这些致病T细胞的机制，并将确定干扰素-a/b是否能阻断这些哮喘患者分离的炎性T细胞分泌细胞因子。这些研究将为更有效、更持久地治疗过敏和哮喘奠定基础。

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.