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及其相关细胞是发育相关的先天免疫细胞 能够执行成功的抗病毒免疫反应所必需的多种功能，包括I型 干扰素分泌和T细胞活化。与私营部门和私营部门有关的身份，即发展和职能 细胞受转录因子(转录因子)的精确相互作用控制。对转录的严格调控 在避免损害健康的同时，促进对病原体的适当反应是必不可少的 纸巾。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- 空间不偏不倚的方法，我们最近发现了两个保守的转录因子，它们是特异的和高度 在PDCs和PDC相关细胞中活跃，但在其他DC亚群中不活跃。在两个具体目标中，我们建议探索 这些因子在决定pDC和pDC相关细胞的发育和功能中的作用。要实现 我们的目标是，我们将利用新的条件性基因敲除小鼠模型，转录因子- 过度表达人类细胞系，以及我们实验室已经建立的高维方法。我们期待着 这项提案的发现将揭示转录调控的新机制，从而导致 针对病毒的先天免疫反应的积极结果。重要的是，我们的综合方法将 融合了对鼠标和人类DC的分析；因此，它可以揭示 物种。这一建议有可能通过探索影响治疗策略的合理设计 决定关键抗病毒先天细胞身份的调控程序。

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.