The role of CD1a-restricted T cells in inflammatory skin diseases

CD1a 限制性 T 细胞在炎症性皮肤病中的作用

• 批准号: 9543606
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-08-23 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9543606
• 关键词: Affect; Allergens; Animal Model; Animals; Antibodies; Antigen Presentation; Antigen-Antibody Complex; Antigens; Autoimmune Diseases; Bacteria; Binding; Blocking Antibodies; CD1 Antigens; CD4 Positive T Lymphocytes; Cells; Complex; Contact Dermatitis; Crystallization; Dendritic Cells; Disease; Disease model; Ear; Future; Generations; Human; Immune response; Immune system; Inflammation; Inflammatory; Interleukin-17; Investigation; Kinetics; Langerhans cell; Lead; Lipid Binding; Lipids; Measurement; Measures; Mediating; Memory; Modeling; Patients; Peptides; Proteins; Psoriasis; Recombinants; Rhus radicans; Rodent; Role; Side; Skin; Source; Specificity; Structure; Swelling; System; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Transgenic Mice; Translating; Tropism; Work; base; cytokine; experimental study; granulocyte; 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. 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 exclusively driven by CD1a-expressing Langerhans cells that elicit the generation of CD4 T cells, producing the inflammatory cytokines IL-17 and IL- 22. In a model for psoriasis, CD1a massively amplifies inflammation mediated by Th17 cells reactive with self lipid antigens from skin. Strikingly, treatment with blocking antibodies against CD1a fully abrogates skin inflammation. These experiments will provide the first in vivo evidence that CD1a on Langerhans cells is essential to control skin inflammation. 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 resolve 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 translate our findings to the human system and demonstrate that poison ivy responders and patients suffering from psoriasis show strong inflammatory T cell activation in response to CD1a. Taken together, we propose CD1a as a novel target for future therapeutic strategies against inflammatory skin diseases.

总结 与识别MHC蛋白上的肽的传统T细胞相反，CD1分子将脂质 T淋巴细胞抗原。CD1a的大量表达标志着皮肤中的朗格汉斯细胞， 具有抗原呈递功能树突状细胞亚型。CD1a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 CD1a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CD1a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CD1a对炎症性皮肤病的影响。为了克服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 皮肤炎症。我们表明，植物毒葛中的有毒物质漆酚会导致严重的皮肤病， 以CD1a依赖的方式炎症。免疫应答完全由表达CD1a的 Langerhans细胞引起CD4 T细胞的产生，产生炎性细胞因子IL-17和IL-18。 22.在银屑病模型中，CD1a大量放大了与自身免疫反应的Th17细胞介导的炎症 来自皮肤的脂质抗原。引人注目的是，用抗CD1a的封闭抗体治疗完全消除了皮肤 炎症这些实验将提供第一个体内证据，证明朗格汉斯细胞上的CD1a是 对控制皮肤炎症至关重要。 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CD1a限制性T细胞的抗原特异性（TCR库）。我们计划开发新的工具， CD1a四聚体和用于CD1a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CD1a的结合。利用结构生物学，我们解析了 CD1a/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CD1a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，我们将我们的发现转化为人类系统，并证明毒藤反应者和 患有银屑病的患者显示出对CD1a的强烈的炎性T细胞活化。采取 总之，我们建议CD1a作为未来治疗炎症性皮肤的新靶点 疾病