Role of Langerhans Cells in the Cutaneous Immune System

描述（由申请人提供）：皮肤树突状细胞（DC）是有效的抗原呈递细胞，是皮肤免疫系统的关键组成部分。最佳表征的皮肤DC亚群是朗格汉斯细胞（LC），其存在于皮肤的表皮中，并且是第一个遇到皮肤病原体、环境损伤和表皮瘤形成的DC群体。研究皮肤DC功能的主要障碍包括：难以准确识别皮肤DC亚群;无法在体内测试DC亚群的功能重要性;以及缺乏可以在体内检查对皮肤抗原的抗原特异性应答的生理模型系统。我们相信，我们已经克服了一些这些障碍，虽然发展转基因小鼠，有一个特定的，完全和持久的缺乏LC。使用皮肤免疫反应的经典测定，我们已经表明，接触性超敏反应（CHS）和同种异体皮肤移植物的排斥反应不需要LC。相反，我们发现在没有LC的情况下，CHS反应和轻微不匹配的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CHS反应所需的新DC亚群的标志物。我们建议利用这些工具来研究LC介导的CHS调控机制。我们将研究LC介导的调节是否发生在稳态或免疫时，以及是否需要LC衍生的IL-10或TGF-2。我们还将通过微阵列比较LC与其他皮肤DC亚群的表达谱。最后，我们将产生一个抗原特异性的感染模型，结合现有的模型，皮肤念珠菌病与白色念珠菌，我们将工程表达卵清蛋白。我们将能够使用这个模型来检查LC是否调节或促进对酵母的免疫反应，以及LC如何影响抗原特异性反应的发展。公共卫生相关性：朗格汉斯细胞和其他皮肤树突细胞是皮肤免疫系统的关键组成部分。它们在产生针对入侵病原体的免疫应答、在皮肤自身免疫性疾病的发展中以及在预防对皮肤病原体的应答中是重要的。我们建议使用我们最近开发的朗格汉斯细胞缺陷小鼠来研究这些细胞功能背后的精确分子机制。

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. PUBLIC HEALTH RELEVANCE: Langerhans cells and other skin dendritic cells are critical components of the immune system in the skin. They are important in generating immune responses against invading pathogens, in the development of skin autoimmune diseases and in preventing responses to commensal skin pathogens. We are proposing to use Langerhans cell deficient mice that we have recently developed to investigate the precise molecular mechanisms that underlie the function of these cells.