特应性皮炎(AD)的发病机制包括皮肤屏障功能改变、免疫应答异常、环境因素刺激等，位于表皮的Langerhnas细胞(LC)是联系上述关键因素的纽带，在AD发病中居于核心地位，但确切的作用和机制尚不明确。一般认为LC参与AD经皮致敏并诱导Th2免疫应答，而我们和其他学者发现LC介导经皮免疫耐受。LC致免疫应答或致免疫耐受功能的调控机制是目前关注的焦点。我们提出假说认为LC的致耐受和致免疫功能由LC不同亚群——组织定居LC(cLC)和单核细胞来源LC(moLC)分别承担，Notch信号途径在调控LC两亚群的分化和功能中发挥关键作用。本研究拟在以往工作基础上，利用LC选择性标记模式小鼠进一步确认LC两亚群，深入分析LC不同亚群在AD炎症中的作用及机制，进一步利用条件性缺失Notch信号的小鼠，研究Notch信号途径在LC分化及功能中的作用，有望阐明LC在AD中的作用及机制、揭示AD治疗的新策略。

Skin barrier dysfucntions, abberrant immune responses and environmental stimulations are the key contributors to the onset of atopic dermatitis (AD). Langerhans Cells (LC), specialized dendritic cells (DCs) in the epidermis of skin, connect the above major contributors and play important roles in the pathogenesis of AD. However, the precise roles and mechanism of LC in AD are not clear yet. It has been proved that LC participate in the epicutaneous immunization of AD by eliciating Th2 immune responses; whereas we and other groups discovered that LC also mediate skin tolerance and maintain the skin homeostasis. Currently the mechanism of skin-immunization versus skin-tolerance mediated by LC is the focus of extensive investigation. We hypothesize that the pro-inflammation and pro-tolerance functions of LC are carried out by two different LC subsets, monocyte-derived LC (moLC) and tissue-resident LC (cLC), which pursue pro-inflammation and pro-tolerance function in the inflammatory and steady state of skin respectively, and Notch signaling pathway might play important roles in the process of LC differentiation or immunization/tolerance induction. In the present proposal, we plan to analyze the role and mechanism of LC subsets in the pathogenesis of AD by ultilizing LC conditional knockout mice, based on our previous studies. We also plan to use mice deficient in molecules of Notch signaling pathway, and explore the function of Notch signaling in the development and function of LC. This study will further our understanding of the pathogenesis of AD, and place a foundation for the future targeting theray for AD.