Function of CD1a on Langerhans cells in skin inflammation

CD1a 对朗格汉斯细胞在皮肤炎症中的作用

• 批准号: 10080031
• 负责人: Florian Winau
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-22 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080031
• 关键词: Affect; Allergens; Anatomy; Animal Model; Animals; Antigen-Antibody Complex; Antigens; Autoimmune Diseases; Bacteria; Binding; CD1 Antigens; CD4 Positive T Lymphocytes; Complex; Contact Dermatitis; Crystallization; Data; Dendritic Cells; Disease; Disease model; Future; Generations; Genetic; Human; Imiquimod; Immune response; Immune system; Inflammation; Inflammatory; Interleukin-17; Investigation; Kinetics; Langerhans cell; Lead; Lipid Binding; Lipids; Measurement; Mediating; Modeling; Mus; Pathogenesis; Patients; Peptides; Proteins; Psoriasis; Rhus radicans; Role; Side; Skin; Source; Specificity; Structure; System; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Therapeutic; Transgenic Mice; Transgenic Organisms; Translating; Work; antigen detection; antigen-specific T cells; base; cytokine; in vivo; interleukin-22; mouse model; new therapeutic target; novel; plant poison; response; skin disorder; structural biology; symptom treatment; tool; urushiol

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.

总结 与识别MHC蛋白上肽的传统T细胞相反，CD 1分子呈现脂质 T淋巴细胞抗原。CD 1a的大量表达标志着皮肤中的朗格汉斯细胞， 具有抗原呈递功能树突状细胞亚型。CD 1a能够结合并显示广谱 来自外源性来源（如细菌）或宿主来源的脂质抗原。复合免疫 皮肤的系统关键地参与对诸如过敏原的外部损伤的反应，以及自身免疫性损伤。 牛皮癣等疾病。然而，CD 1a在朗格汉斯细胞中的体内作用仍然是个谜，因为 CD 1a在人类中表达，但在大多数动物模型中缺乏。 我们的假设是，朗格汉斯细胞上的CD 1a对控制炎症性皮肤病至关重要。我们将 支持这一假设，具体目标如下： 1)研究CD 1a对炎症性皮肤病的影响。为了克服CD 1a缺乏的障碍， 正常实验动物，我们建议使用人CD 1a转基因小鼠来研究CD 1a对 皮肤炎症。在初步的数据中，我们表明，从植物毒葛中提取的有毒物质漆酚 以CD 1a依赖的方式诱导严重的皮肤炎症。免疫反应由CD 1a驱动- 表达朗格汉斯细胞，其引起CD 4 T细胞的产生，产生炎性细胞因子IL-10， 17和IL-22。基于这些发现，我们建议研究CD 1a在模型中的体内功能， 银屑病使用我们的CD 1a转基因系统。 2)阐明皮肤炎症中脂质的递呈和识别机制。为此，我们将 分析CD 1a限制性T细胞的抗原特异性（TCR库）。我们计划开发新的工具， CD 1a四聚体和用于CD 1a分子的脂质负载的新技术。此外，我们将开发新的动能 测量脂质与CD 1a的结合。利用结构生物学，我们解析了 CD 1a/漆酚复合物。这为随后的三元复合物的结构研究奠定了基础。 TCR和CD 1a呈递的脂质，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为人类系统，并调查毒藤反应者， 银屑病患者的T细胞反应，由CD 1a介导。最后，我们 提出CD 1a作为未来针对炎症性皮肤病的治疗策略的新靶点。