CD6: Thymic Selection and Immune Response

CD 6是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。我们推测，CD 6的主要作用是共同刺激胸腺细胞和成熟的T细胞在低功能性酸度与MHC/抗原复合物的相互作用。在转基因小鼠中CD 6的过度表达被假设导致胸腺细胞和成熟淋巴细胞的表型和功能的改变。本申请的重点是确定CD 6在胸腺细胞选择和成熟T细胞的抗原应答中的功能。我们的具体目标是：1）表征我们的表达人CD 6和过表达总CD 6的新转基因小鼠的表型; 2）检验在胸腺中，CD 6依赖性共刺激增加胸腺细胞选择的假设; 3）检验在外周中，成熟T细胞的CD 6依赖性共刺激微调它们对特异性抗原的应答的假设。CD 6的表达可能通过增加自反应性胸腺细胞的选择、增加对细胞凋亡的抵抗力和/或天然T细胞以及降低成熟T细胞对自身抗原的刺激阈值来促进自身免疫。为了定义CD 6的功能，我们将使用互补的“功能获得”和“功能丧失”方法，包括培育为缺乏或过度表达CD 6的小鼠，与抗原特异性TCR转基因小鼠、胸腺器官培养物和抑制CD 6/CD 6配体相互作用的特异性可溶性试剂组合。我们的长期目标是了解CD 6在自身免疫中的作用。自身免疫治疗中的主要问题之一是目前的疗法同时降低自身免疫和保护性免疫。我们最终想确定抑制CD 6/CD 6L相互作用是否可以选择性地抑制与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性抗原的反应。

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 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.