CD6: Thymic Selection and Autoimmunity

CD6：胸腺选择和自身免疫

基本信息

批准号：
6399112
负责人：
NORA SINGER
金额：
$ 33.98万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2002-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6399112
关键词：
CD antigens T cell receptor T lymphocyte antigen antibody reaction apoptosis autoimmunity developmental immunology genetically modified animals human fetus tissue human tissue laboratory mouse major histocompatibility complex molecular cloning receptor binding thymus

项目摘要

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 costimulate thymocytes and mature T-cells during low functional avidity interactions with MHC/antigen complexes and to augment resistance of these cells to apoptosis. Mechanisms by which CD6 may contribute to autoimmunity include increased selection of self-reactive thymocytes, increased resistance of thymocytes and/or mature T-cells to apoptosis, and decreases in the stimulation threshold of mature T-cells to self-antigens. We will use complimentary "gain of function" and "loss of function" approaches, including mice bred either to lack or to overexpress CD6, in combination with antigen-specific TCR transgenic mice, thymic organ cultures, and specific soluble reagents which inhibit CD6/CD6 ligand interactions. Potential excesses in CD6-dependent costimulation could also occur if CD6 ligands are over-expressed during T-cell development and/or in tissues affected by autoimmunity. We have identified a new CD6 ligand that is expressed in the thymus, in skin and in synovium. We plan to clone this new CD6 ligand and to study its expression on thymic epithelium during T-cell development. Our specific aims are 1) to test the hypothesis that CD6-dependent costimulation to thymocytes increases functional avidity for AMC/antigen complexes and/or resistance to apoptosis; 2) to test the hypothesis that CD6-dependent costimulation to mature T-cells increases functional avidity and/or resistance to apoptosis; and 3) to clone the novel CD6 ligand and characterize its expression in the thymus. Our long-term goal is to understand the role of CD6 in immunity. One of the major problems in the treatment 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是一种以发育胸腺细胞和成熟的T细胞表示的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性相互作用期间，在胸腺细胞和成熟的T细胞中添加胸腺细胞和成熟的T细胞，并增强这些细胞对凋亡的耐药性。 CD6可能导致自身免疫性的机制包括增加自反应性胸腺细胞的选择，胸腺细胞的耐药性和/或成熟的T细胞对凋亡的耐药性，以及对自身抗原成熟T细胞的刺激阈值的降低。我们将使用免费的“功能获得”和“功能丧失”方法，包括繁殖为缺乏或过表达CD6的小鼠，结合抗原特异性TCR转基因小鼠，胸腺器官培养物以及抑制CD6/CD6配体相互作用的特定可溶性试剂。如果在T细胞发育和/或受自身免疫性影响的组织中过度表达CD6配体，CD6依赖性共霉菌的潜在过量也可能发生。我们已经确定了一种新的CD6配体，该配体在胸腺，皮肤和滑膜中表达。我们计划克隆这种新的CD6配体，并研究其在T细胞发育过程中对胸腺上皮的表达。我们的具体目的是1）检验以下假设：CD6依赖性对胸腺细胞的共刺激增加了AMC/抗原复合物和/或对凋亡的抗性的功能亲和力； 2）检验以下假设：CD6依赖于成熟T细胞的共刺激会增加功能性亲和力和/或对凋亡的抗性； 3）克隆新颖的CD6配体并表征其在胸腺中的表达。我们的长期目标是了解CD6在免疫中的作用。自身免疫治疗的主要问题之一是，当前疗法同时降低了自身免疫性和保护性免疫力。我们最终想确定抑制CD6/CD6L相互作用是否可以选择性地抑制较弱的自我抗原反应性，而不会损害对先天免疫力很重要的较强的外源抗原的反应。