Function of CD1a on Langerhans cells in skin inflammation

摘要 与识别MHC蛋白上的多肽的传统T细胞不同，CD1分子代表脂质 T淋巴细胞的抗原。CD1a的大量表达标志着皮肤中的朗格汉斯细胞 具有抗原提呈功能的树突状细胞亚型。CD1a能够结合并展示广谱 来自外部来源的脂类抗原，如细菌，或宿主来源。复杂的免疫 皮肤系统在对外来侮辱(如过敏原)的反应以及自身免疫中起着关键作用。 疾病，如牛皮癣。然而，CD1a在朗格汉斯细胞中的体内作用仍然是个谜，因为 CD1a在人类中有表达，但在大多数动物模型中缺乏。 我们的假设是郎格汉斯细胞上的CD1a对于控制炎症性皮肤病至关重要。我们会 支持这一假设的具体目的如下： 1)探讨CD1a在炎症性皮肤病中的作用。克服CD1a缺乏的障碍 正常实验动物，我们建议使用人CD1a转基因小鼠来研究CD1a对血管内皮细胞生长的影响。 皮肤发炎。在初步数据中，我们表明，来自植物毒藤的脂类物质漆酚 以CD1a依赖的方式诱导严重的皮肤炎症。免疫反应由CD1a驱动- 表达诱导产生CD4T细胞的朗格汉斯细胞，产生炎性细胞因子IL-2 17和IL-22。在这些发现的基础上，我们建议研究CD1a在动物模型中的体内功能 使用我们的CD1a转基因系统治疗银屑病。 2)阐明皮肤炎症中脂质呈递和识别的机制。为此，我们将 分析CD1a限制性T细胞的抗原特异性(TCR谱系)。我们计划生成新的工具，如 CD1a四聚体和CD1a分子脂质负载的新技术。此外，我们还将开发新的动力 脂类与CD1a结合的测定。利用结构生物学，我们解析了化合物的晶体结构 CD1a/漆酚复合体。这为后续对三元络合物的结构研究奠定了基础 CD1a提供的TCR和脂质，也将有助于识别炎症皮肤中的主要脂质抗原 疾病。 最后，我们的目标是将我们的发现转化到人类系统中，并调查毒藤响应者和 银屑病患者CD1a介导的T细胞应答总之，我们 建议将CD1a作为未来炎症性皮肤病治疗策略的新靶点。

Summary In contrast to conventional T cells that recognize peptides on MHC proteins, CD1 molecules present lipid antigens to T lymphocytes. The abundant expression of CD1a hallmarks Langerhans cells in the skin, a subtype of dendritic cell with antigen-presenting functions. CD1a is able to bind and display a broad spectrum of lipid antigens derived from exogenous sources, such as bacteria, or host origin. The complex immune system of the skin is critically involved in responses to extrinsic insults like allergens, as well as in autoimmune diseases, such as psoriasis. However, the in vivo role of CD1a on Langerhans cells remains enigmatic, since CD1a is expressed in humans but lacking in most animal models. Our hypothesis is that CD1a on Langerhans cells is critical to control inflammatory skin diseases. We will support this hypothesis with the following specific aims: 1) Investigate the impact of CD1a on inflammatory skin diseases. To overcome the obstacle of CD1a lacking in normal experimental animals, we propose to use human CD1a-transgenic mice to study the impact of CD1a on skin inflammation. In preliminary data, we show that the lipidic substance urushiol from the plant poison ivy induces severe skin inflammation in a CD1a-dependent fashion. The immune response is driven by CD1a- expressing Langerhans cells that elicit the generation of CD4 T cells, producing the inflammatory cytokines IL- 17 and IL-22. Based on these findings, we propose to investigate the in vivo functions of CD1a in models of psoriasis using our CD1a-transgenic system. 2) Elucidate the mechanism of lipid presentation and recognition in skin inflammation. For this purpose, we will analyze antigen specificity (TCR repertoire) of CD1a-restricted T cells. We plan to generate new tools such as CD1a tetramers and novel techniques for lipid loading of CD1a molecules. Further, we will develop new kinetic measurements for binding of lipids to CD1a. Using structural biology, we resolved the crystal structure of the CD1a/urushiol complex. This forms the basis for subsequent structural studies on the ternary complex between TCR and lipids presented by CD1a, and will also help to identify dominant lipid antigens in inflammatory skin diseases. Finally, we aim to translate our findings to the human system and investigate poison ivy responders and patients suffering from psoriasis with regard to their T cell responses mediated by CD1a. To conclude, we propose CD1a as a novel target for future therapeutic strategies against inflammatory skin diseases.