Molecular Control of Plasmacytoid Dendritic Cell Development and Function

血浆细胞样树突状细胞(PDCs)能快速分泌I型干扰素(干扰素α/β)，以应对病毒感染。 衍生核酸，促进先天和获得性抗病毒反应。相反，反常的干扰素 PDC的产生与自身免疫性疾病有关，使pDC成为重要的新兴疾病 治疗靶点。本项目的总体目标是阐明pDC谱系的分子调控。 包括它的发育、动态平衡和在各种免疫反应中的作用。在前一个奖项中 周期，我们已经确定E蛋白转录因子TCF4(E2-2)和其他几个因素是重要的 PDC开发的监管机构。拟议的工作将以这些调查结果为基础，以解决主要 PDC生物学中悬而未决的问题。在目标1中，我们将使用高维单细胞分析方法 以表征PDC谱系规范的阶段和调节，以及功能异质性 成熟的PDDC。在目标2中，我们将使用遗传方法来剖析转录控制和调控 PDC独特的干扰素产生能力。在目标3中，我们将探索病毒识别和 PDC体内产生干扰素。总的来说，拟议的研究应该产生一个全面的分子 观察PDC的发育和功能，为以这种细胞类型为重点的治疗方法铺平道路。 相关性(请参阅说明)： 浆细胞样树突状细胞(PDC)在免疫应答中发挥重要作用。 自身免疫，因此是新型免疫特异体的有吸引力的靶点。拟议的工作目标 构建PDC发展和功能的全面分子观，为PDC的重点铺平道路 人类疾病中的转译方法。

Plasmacytoid dendritic cells (pDCs) rapidly secrete type I interferon (interferon α/β, IFN) in response to virus- derived nucleic acids, facilitating both innate and adaptive antiviral responses. Conversely, aberrant IFN production by pDCs is associated with autoimmune diseases, establishing pDCs as important emerging therapeutic targets. The overall goal of this project is to elucidate the molecular control of pDCs lineage, including its development, homeostasis and function in various immune responses. In the previous award cycles, we have identified E protein transcription factor TCF4 (E2-2) and several other factors as important regulators of pDC development. The proposed work will build upon these findings to address major unanswered questions in pDC biology. In Aim 1, we will use high-dimensional single-cell analysis methods to characterize the stage and regulation of pDC lineage specification, as well as the functional heterogeneity of mature pDCs. In Aim 2, we will use genetic approaches to dissect transcriptional control and regulation of the unique IFN-producing capacity of pDCs. In Aim 3, we will explore the mechanism of virus recognition and IFN production by pDCs in vivo. Collectively, the proposed studies should yield a comprehensive molecular view of pDC development and function, paving the way for therapeutic approaches focused on this cell type. RELEVANCE (See instructions): Plasmacytoid dendritic cells (pDCs) play an important role in immune responses to infection and in autoimmunity, and therefore represent attractive targets for novel immunoterapies. The proposed work aims to build a comprehensive molecular view of pDC development and function, paving the way for pDCfocused translational approaches in human diseases.