Type 1 Interferon-Regulated T Helper Development

1 型干扰素调节 T 辅助细胞的发育

• 批准号: 7174846
• 负责人: John David FARRAR
• 金额: $ 29.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174846
• 关键词: Antiviral Response; Attention; B-Lymphocytes; Bacterial Infections; Biochemical Pathway; CD4 Positive T Lymphocytes; Cells; Chronic Hepatitis; Cytomegalovirus; Data; Development; Disease; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Human; Immune response; Immunity; Immunoglobulins; Infection; Interferon Type I; Interferon Type II; Interferon-alpha; Interferons; Interleukin-12; Interleukin-4; Lead; Link; Molecular; Multiple Sclerosis; Mus; Mutation; Nature; Neoplasms; Pathway interactions; Pattern; Personal Satisfaction; Phenotype; Play; Process; Production; Receptor Signaling; Research Personnel; Role; STAT4 protein; Sentinel; Shapes; Signal Pathway; Signal Transduction; Source; T-Lymphocyte; Testing; Th2 Cells; Vaccinia virus; Viral; Virus Diseases; Virus Replication; base; cytokine; mouse model; pathogen; programs; response; transcription factor

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.

描述（由申请人提供）：I 型干扰素 (IFN-α/Beta) 是先天性和适应性免疫的重要调节剂，并提供针对病毒和细菌感染的第一个细胞内屏障之一。 IFN-α/β还用于治疗慢性肝炎、多发性硬化症和多种肿瘤等疾病。这些过程还没有被很好地理解，因为当前的小鼠模型无法概括在人类中发挥作用的 IFN-α/Beta 反应的许多重要方面。例如，在人类中，IFN-α/Beta 通过激活关键转录因子 Stat4 来促进 IFN-γ 分泌。然而，IFN-α/Beta 不会诱导小鼠 Th1 发育，因为 IFN-a/p 不会激活小鼠 T 细胞中的 Stat4。基于 IFN-α/Beta 在调节先天性和适应性免疫反应中的重要性以及 IFN-α/Beta 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 IFN- 的反应。人类 T 细胞中的 α/β。该途径的诱导导致对病原体的独特免疫反应，从而在人类感染期间引发 IFN-α/β 的产生。此外，该途径赋予人类 CD4+ T 细胞独特的表型和基因表达模式，而在小鼠中未发现。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。目标 2 将表征 IFN-α/β 驱动的 T 细胞的效应功能，包括溶细胞活性、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。在目标 3 中，我们将确定特定信号通路和转录因子在调节 IFN-α/β 依赖性 T 辅助细胞发育中所起的作用。这项研究将为理解在感染初期主要诱导 IFN-α/β 的病原体的先天反应和适应性反应之间的联系提供一个非常重要的框架。