Genetic Approaches to the Study of Plasmacytoid Dendritic Cell Function

描述（由申请人提供）：浆细胞样树突状细胞（PDC）是一种独特的细胞类型，在先天和适应性免疫反应中起关键作用。在病毒感染期间，PDC分泌大量I型干扰素（IFN），以及呈现病毒抗原和初始T细胞反应。除抗病毒免疫外，PDC还与许多免疫现象有关，包括对口服抗原和同种异体移植物的耐受、过敏性炎症、抗肿瘤免疫和自身免疫。在后一种情况下，PDC要么通过异常IFN分泌促进自身免疫性疾病，要么通过调节T细胞分化来抵消自身免疫性疾病。因此，PDC在自身免疫等长期免疫反应中的确切作用仍有待阐明。这项任务需要开发新的遗传方法，例如本型PDC谱系消融系统。我们的实验室最近发现转录因子E2-2是小鼠和人类PDC发育的关键调节因子。我们建议使用E2-2的条件靶向作为稳态本构PDC烧蚀的工具。在Specific Aim 1中，E2-2条件敲除小鼠将以PDC消融的效率和特异性、IFN分泌能力和抗病毒免疫反应为特征。在Specific Aim 2中，将使用产生的“PDC-less”小鼠来探索PDC在自身免疫神经炎症和狼疮样自身免疫的自发动物模型中的作用。这些研究将为PDC的研究提供一个新的实验系统，并为PDC在自身免疫性疾病中的作用提供见解。

DESCRIPTION (provided by applicant): Plasmacytoid dendritic cells (PDC) represent a unique cell type that plays a critical role in both innate and adaptive immune responses. During viral infection, PDC secrete massive amounts of type I interferon (IFN), as well as present viral antigens and prime T cell responses. In addition to antiviral immunity, PDC have been implicated into many immunological phenomena, including tolerance to oral antigens and allografts, allergic inflammation, antitumor immunity and autoimmunity. In the latter case, PDC were proposed to either promote autoimmune disease through aberrant IFN secretion or counteract it by modulating T cell differentiation. Thus, the precise function of PDC in prolonged immune reactions such as autoimmunity remains to be elucidated. This task calls for the development of novel genetic approaches, such as systems for constitutive PDC lineage ablation. Our lab has recently identified transcription factor E2-2 as a critical regulator of PDC development in mice and humans. We propose to use conditional targeting of E2-2 as a tool for constitutive PDC ablation in the steady state. In Specific Aim 1, E2-2 conditional knockout mice will be characterized for the efficiency and specificity of PDC ablation, and for their IFN secretion capacity and antiviral immune responses. In Specific Aim 2, the resulting "PDC-less" mice will be used to probe the role of PDC in spontaneous animal models of autoimmune neural inflammation and of lupus-like autoimmunity. These studies would generate a novel experimental system for the study of PDC, and provide insights into the role of PDC in autoimmune diseases. PUBLIC HEALTH RELEVANCE: The study is aimed at the functional analysis of plasmacytoid dendritic cells (PDC), a unique immune cell type that plays a major role in antiviral immunity and other immune responses. The development of a novel genetic model for constitutive PDC ablation would facilitate the study of PDC function and provide insights into the role of PDC in autoimmune diseases such as multiple sclerosis and lupus.