CD6: Thymic Selection and Autoimmunity

CD6是一种t细胞共刺激分子，在发育中的胸腺细胞和成熟的t细胞上表达。我们假设CD6的主要作用是在与MHC/抗原复合物的低功能相互作用中共同刺激胸腺细胞和成熟t细胞，并增强这些细胞对凋亡的抵抗力。CD6可能促进自身免疫的机制包括增加对自身反应性胸腺细胞的选择，胸腺细胞和/或成熟t细胞对凋亡的抵抗力增加，成熟t细胞对自身抗原的刺激阈值降低。我们将使用互补的“功能获得”和“功能丧失”方法，包括培养缺乏或过表达CD6的小鼠，结合抗原特异性TCR转基因小鼠，胸腺器官培养和抑制CD6/CD6配体相互作用的特异性可溶性试剂。如果CD6配体在t细胞发育和/或受自身免疫影响的组织中过度表达，也可能发生CD6依赖性共刺激的潜在过度。我们已经确定了一种新的CD6配体，它在胸腺、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细胞发育过程中在胸腺上皮上的表达。我们的具体目标是：1)验证对胸腺细胞的cd6依赖性共刺激增加AMC/抗原复合物的功能亲和力和/或细胞凋亡抗性的假设；2)验证对成熟t细胞的cd6依赖性共刺激增加功能亲和性和/或抗凋亡的假设；3)克隆新的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。治疗自身免疫的主要问题之一是目前的治疗方法同时降低了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对较弱自身抗原的反应性，而不影响对先天免疫中重要的较强外源抗原的反应。

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.