Type 1 Interferon-Regulated T Helper Development

描述（由申请人提供）：I型干扰素（IFN-α/β）是先天性和适应性免疫的重要调节剂，并为病毒和细菌感染提供了第一个细胞内屏障。IFN-α/β也用于治疗慢性肝炎、多发性硬化和各种肿瘤等疾病。这些过程没有得到很好的理解，因为目前的小鼠模型未能概括在人类中起作用的IFN-α/β应答的许多重要方面。例如，在人类中，IFN-α/β通过激活关键转录因子Stat 4来促进IFN-γ分泌。然而，IFN-α/β不诱导小鼠中的Th 1发育，因为IFN-α/β不激活鼠T细胞中的Stat 4。基于IFN-α/β在调节先天性和适应性免疫应答中的重要性以及IFN-α/β信号传导的物种特异性，本研究的目标是充分表征人T细胞中CD 4+适应性T细胞对IFN-α/β的应答。该途径的诱导导致对病原体的独特免疫应答，所述病原体在人类感染期间引起IFN-α/β产生。此外，该途径赋予了在小鼠中未发现的人CD 4 + T细胞中的独特表型和基因表达模式。在本提案的目标1中，我们将通过基因表达谱分析和细胞因子表达模式分析来鉴定IFN-α/β诱导的发育途径。目的2将表征IFN-α/β驱动的T细胞的效应子功能，包括细胞溶解活性、使用牛痘病毒抑制病毒复制和支持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IFN-α/β依赖性T辅助细胞发育中的作用。这项研究将提供一个非常重要的框架，了解先天性和适应性反应之间的联系，病原体主要诱导IFN-α/β在感染的初始阶段。

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.