CD6: Thymic Selection and Immune Response

CD6：胸腺选择和免疫反应

• 批准号: 6847788
• 负责人: NORA SINGER
• 金额: $ 33.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847788
• 关键词: CD antigens; T cell receptor; T lymphocyte; antigen antibody reaction; apoptosis; autoantigens; autoimmunity; developmental immunology; genetically modified animals; laboratory mouse; leukopoiesis; major histocompatibility complex; thymus

CD6 is a T-cell costimulatory molecule expressed on developing thymocytes and on mature T-cells. We hypothesize that a major role of CD6 is to co-stimulate thymocytes and mature T-cells during low functional acidity interactions with MHC/antigen complexes. Over- expression of CD6 in transgenic mice is hypothesized to lead to alteration of the phenotype and function of both thymocytes and mature lymphocytes. The focus of this application is to determine the function of CD6 in thymocyte selection and antigen responses of mature T-cells. Our specific aims are: 1) To characterize the phenotype of our new transgenic mice that express human CD6 and over-express total CD6 2) To test the hypothesis that in the thymus, CD6- dependent co-stimulation increases thymocyte selection; 3) To test the hypothesis that in the periphery, CD6-dependent co-stimulation of mature T-cells fine tunes their response to specific antigen. Expression of CD6 may contribute to autoimmunity through increased selection of self-reactive thymocytes, increased resistance and/or nature T-cells to apoptosis, and decreases in the stimulation threshold of mature T-cells to self-antigens. To define the function(s) o CD6 we will use complimentary "gain of function" and "loss of function" approaches, including mice bred either to lack or to over-express CD6, in combination with antigen-specific TCR transgenic mice, thymic organ cultures, and specific soluble reagents which inhibit CD6/CD6 ligand interactions. Our long-term goal is to understand the role of CD6 in autoimmunity. One of the major problems in the treatments of autoimmunity is that current therapies reduce both autoimmunity and protective immunity simultaneously. We ultimately want to determine if inhibiting CD6/CD6L interactions can selectively inhibit reactivity with weaker self-antigens without compromising responses to stronger exogenous antigens that are important in innate immunity.

CD6 是一种在发育中的胸腺细胞和成熟 T 细胞上表达的 T 细胞共刺激分子。我们假设 CD6 的主要作用是在与 MHC/抗原复合物的低功能酸度相互作用期间共同刺激胸腺细胞和成熟 T 细胞。据推测，转基因小鼠中CD6的过度表达会导致胸腺细胞和成熟淋巴细胞的表型和功能的改变。本应用的重点是确定 CD6 在胸腺细胞选择和成熟 T 细胞抗原反应中的功能。我们的具体目标是： 1) 表征表达人 CD6 和过表达总 CD6 的新型转基因小鼠的表型 2) 检验胸腺中 CD6 依赖性共刺激增加胸腺细胞选择的假设； 3) 检验以下假设：在外周，成熟 T 细胞的 CD6 依赖性共刺激可微调其对特定抗原的反应。 CD6的表达可能通过增加自身反应性胸腺细胞的选择、增加T细胞对凋亡的抵抗力和/或天然性以及降低成熟T细胞对自身抗原的刺激阈值来促进自身免疫。为了定义 CD6 的功能，我们将使用互补的“功能获得”和“功能丧失”方法，包括培育缺乏或过度表达 CD6 的小鼠，结合抗原特异性 TCR 转基因小鼠、胸腺器官培养物和抑制 CD6/CD6 配体相互作用的特异性可溶性试剂。我们的长期目标是了解 CD6 在自身免疫中的作用。自身免疫治疗的主要问题之一是当前的疗法同时降低自身免疫和保护性免疫。我们最终想要确定抑制 CD6/CD6L 相互作用是否可以选择性地抑制与较弱自身抗原的反应，而不损害对先天免疫中重要的较强外源抗原的反应。