Type 1 Interferon-Regulated T Helper Development

描述（由申请人提供）：I型干扰素（ifn - α / β）是先天免疫和适应性免疫的重要调节剂，是抵抗病毒和细菌感染的第一个细胞内屏障之一。ifn - α / β也用于治疗慢性肝炎、多发性硬化症和各种肿瘤等疾病。这些过程还没有被很好地理解，因为目前的小鼠模型不能概括在人类中运作的ifn - α / β反应的许多重要方面。例如，在人类中，ifn - α / β通过激活关键转录因子Stat4来促进ifn - γ的分泌。然而，ifn - α / β在小鼠中不会诱导Th1的发育，因为IFN-a/p不会激活小鼠T细胞中的Stat4。基于ifn - α / β在调节先天和适应性免疫反应中的重要性，以及ifn - α / β信号传导的物种特异性，本研究的目标是全面表征CD4+适应性T细胞对人类T细胞中ifn - α / β的反应。这一途径的诱导导致对病原体的独特免疫反应，在人类感染期间引发ifn - α / β的产生。此外，这一途径赋予人类CD4+ T细胞独特的表型和基因表达模式，而这些在小鼠中没有发现。在本提案的目标1中，我们将通过基因表达谱和细胞因子表达模式分析来确定ifn - α / β诱导的发育途径。目的2将表征ifn - α / β驱动的T细胞的效应功能，包括细胞溶解活性，使用牛痘病毒抑制病毒复制，以及支持B细胞免疫球蛋白分泌。在Aim 3中，我们将确定特定的信号通路和转录因子在调节ifn - α / β依赖性T辅助发育中的作用。这项研究将为理解在感染初期主要诱导ifn - α / β的病原体的先天和适应性反应之间的联系提供一个非常重要的框架。

DESCRIPTION (provided by applicant): Type I interferon (IFN-alpha/Beta) is an important modulator of both innate and adaptive immunity and provides one of the first intracellular barriers to viral and bacterial infections. IFN-alpha/Beta is also used to treat such diseases as chronic hepatitis, multiple sclerosis, and a variety of neoplasias. These processes are not well understood because current mouse models fail to recapitulate many important aspects of IFN-alpha/Beta responses that operate in humans. For example, in humans, IFN-alpha/Beta promotes IFN-gamma secretion by activating a key transcription factor, Stat4. However, IFN-alpha/Beta does not induce Th1 development in the mouse because IFN-a/p does not activate Stat4 in murine T cells. Based on the importance of IFN-alpha/Beta in regulating both innate and adaptive immune responses and the species-specific nature of IFN-alpha/Beta signaling, the goals of this study are to fully characterize the CD4+ adaptive T cell response to IFN-alpha/Beta in human T cells. Induction of this pathway leads to unique immunological responses to pathogens that elicit IFN-alpha/beta production during infection in humans. Further, this pathway confers unique phenotypes and patterns of gene expression in human CD4+ T cells that are not found in mice. In Aim 1 of this proposal, we will identify IFN-alpha/beta induced developmental pathways through gene expression profiling and analysis of cytokine expression patterns. Aim 2 will characterize effector functions of IFN-alpha/Beta-driven T cells including cytolytic activity, inhibition of viral replication with the use of vaccinia virus, and support of B cell immunoglobulin secretion. In Aim 3, we will determine the role that specific signaling pathways and transcription factors play in regulating IFN-alpha/beta-dependent T helper development. This study will provide a very important framework for understanding the link between innate and adaptive responses to pathogens that primarily induce IFN-alpha/Beta during initial periods of infection.