Role of Langerhans Cells in the Cutaneous Immune System

描述(申请人提供)：皮肤树突状细胞(DC)是有效的抗原提呈细胞，是皮肤免疫系统的关键组成部分。最具特征性的皮肤DC亚群是位于皮肤表皮的朗格汉斯细胞(LC)，它是第一个遇到皮肤病原体、环境侮辱和表皮肿瘤的DC群体。研究皮肤DC功能的主要障碍包括：准确识别皮肤DC亚群的困难；无法在体内测试DC亚群的功能重要性；以及缺乏能够在体内检测对皮肤抗原的抗原特异性反应的生理模型系统。我们相信，我们已经克服了其中的一些障碍，通过开发出具有特定、完全和持久的LC缺失的转基因小鼠。使用经典的皮肤免疫反应分析，我们已经证明，接触性超敏反应(CHS)和异体皮肤移植的排斥反应不需要LC。相反，我们发现，在没有LC的情况下，CHS反应和微小不相合皮肤移植物的排斥反应增强。此外，我们最近还发现了识别真皮中有效的CHS反应所需的新的DC亚群的标记。我们建议利用这些工具来研究LC介导的CHS调节机制。我们将检查LC介导的调节是发生在稳定状态还是在免疫时，以及是否需要LC来源的IL-10或TGF2。我们还将通过基因芯片将LC与其他皮肤DC亚群的表达谱进行比较。最后，我们将通过将现有的皮肤念珠菌病模型与我们将工程表达卵白蛋白的白色念珠菌相结合来生成抗原特异性感染模型。我们将能够使用这个模型来研究LC是否调节或促进对酵母菌的免疫反应，以及LC如何影响抗原特异性反应的发展。

DESCRIPTION (provided by applicant): Skin dendritic cells (DC) are efficient antigen-presenting cells that are a critical component of the cutaneous immune system. The best characterized skin DC subset is the Langerhans cell (LC) that resides in the epidermis of the skin and is the first DC population to encounter cutaneous pathogens, environmental insults and epidermal neoplasia. Major obstacles to studying the function of skin DC include: the difficulty in accurately identifying skin DC subsets; the inability to test the functional importance of DC subsets in vivo; and the absence of a physiologic model system in which antigen-specific responses to cutaneous antigens can be examined in vivo. We believe that we have overcome some of these obstacles though the development transgenic mice that have a specific, complete and durable absence of LC. Using classic assays of the cutaneous immune response we have shown that contact hypersensitivity (CHS) and rejection of allogeneic skin grafts do not require LC. Instead, we found that CHS responses and rejection of minor-mismatched skin grafts were enhanced in the absence of LC. Moreover, we have also recently discovered markers that identify a novel DC subset in the dermis that is required for efficient CHS responses. We propose to exploit these tools to examine the mechanism of LC-mediated regulation of CHS. We will examine whether LC-mediated regulation occurs during the steady-state or at the time of immunization and whether LC-derived IL-10 or TGF2 are required. We will also compare the expression profile of LC with other skin DC subsets by microarray. Finally, we will generate an antigen-specific infection model by combining an existing model of cutaneous Candidiasis with Candida albicans that we will engineer to express ovalbumin. We will be able to use this model to examine whether LC regulate or promote immune responses to yeast and how LC affect the development of antigen-specific responses.