Type 1 Interferon-Regulated T Helper Development

描述(申请人提供)：I型干扰素(干扰素-α/β)是天然免疫和获得性免疫的重要调节剂，是病毒和细菌感染的第一批细胞内屏障之一。干扰素-α/β还用于治疗慢性肝炎、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工作的干扰素-α/贝塔反应的许多重要方面。例如，在人类中，干扰素-α/β通过激活关键转录因子STAT4来促进干扰素-γ的分泌。然而，由于干扰素-α/β不能激活小鼠T细胞中的STAT4，因此干扰素-α/β不能诱导小鼠体内Th1细胞的发育。基于干扰素-α/β在调节先天免疫反应和获得性免疫反应中的重要性以及干扰素-α/β信号的物种特异性，本研究的目的是全面研究人类T细胞中的CD4+适应性T细胞对干扰素-α/β的反应。这一途径的诱导导致了对病原体的独特免疫反应，这些病原体在人类感染期间诱导了干扰素-α/β的产生。此外，这一途径赋予了人类CD4+T细胞独特的表型和基因表达模式，这是在小鼠中找不到的。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的分析来确定干扰素-α/β诱导的发育途径。目的2描述干扰素-α/β-T细胞的效应功能，包括杀伤细胞活性、利用痘苗病毒抑制病毒复制以及支持B细胞免疫球蛋白分泌。在目标3中，我们将确定特定的信号通路和转录因子在调节依赖干扰素-α/β的T辅助细胞发育中所起的作用。这项研究将为理解在感染初期主要诱导干扰素-α/β的病原体的先天反应和获得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.