Novel transcription factors modulating the development and function of pDCs and pDC-related cells

摘要 浆细胞样树突状细胞（Plasmacytoid dendritic cells，pDC）和pDC相关细胞是与发育相关的先天性免疫细胞 能够执行成功的抗病毒免疫应答所必需的多种功能，包括I型 干扰素分泌和T细胞活化。身份，即，pDC和pDC相关基因的发育和功能 细胞的转录是由转录因子（TF）的精确相互作用控制的。转录的严格调控 计划对于促进对病原体的适当反应，同时避免损害健康至关重要。 组织中因此，解开pDC和pDC相关细胞的转录调控是至关重要的。使用高- 维无偏的方法，我们最近发现了两个保守的TF，是具体的和高度 在pDC和pDC相关细胞中有活性，但在其他DC亚群中无活性。在两个具体目标中，我们建议探索 这些TF在决定pDC和pDC相关细胞的发育和功能中的作用。实现 我们的目标是，我们将利用新的条件性敲除小鼠模型，转录因子， 过表达人类细胞系，以及我们实验室已经建立的高维方法。我们预计 这项提议的发现将揭示新的转录调控机制， 先天免疫反应对病毒的积极结果。重要的是，我们的综合方法将 结合小鼠和人DC两者的分析;因此，它可以揭示小鼠和人DC之间保守的特征， 物种该建议有可能通过探索影响治疗策略的合理设计， 确定关键抗病毒先天细胞的身份的调节程序。

ABSTRACT Plasmacytoid dendritic cells (pDCs) and pDC-related cells are developmentally related innate immune cells capable of performing multiple functions essential for successful antiviral immune responses, including type I interferon secretion and T cell activation. The identity, i.e., development and function, of pDCs and pDC-related cells is controlled by the precise interaction of transcription factors (TFs). Tight regulation of transcriptional programs is essential to promote the appropriate response to pathogens while avoiding damage to healthy tissues. Thus, it is critical to unravel the transcriptional regulation of pDCs and pDC-related cells. Using a high- dimensional unbiased approach, we have recently discovered two conserved TFs that are specific and highly active in pDCs and pDC-related cells but not in other DC subsets. In two specific aims, we propose to explore the role of these TFs in determining the development and function of pDCs and pDC-related cells. To achieve our goal, we will take advantage of novel conditional knockout mouse models, transcription factor- overexpressing human cell lines, and high-dimensional approaches already established in our lab. We anticipate that findings from this proposal will bring into light novel mechanisms of transcriptional regulation that result in the positive outcome of innate immune responses against viruses. Importantly, our integrated approach will incorporate analyses of both mouse and human DCs; thus, it can reveal features that are conserved between species. This proposal has the potential to impact the rational design of therapeutic strategies by exploring regulatory programs determining the identity of key antiviral innate cells.