CD6: Thymic Selection and Immune Response

CD6是一种T细胞共刺激分子，表达于发育中的胸腺细胞和成熟的T细胞上。我们假设CD6的主要作用是在低功能酸度下与MHC/抗原复合体相互作用时共同刺激胸腺细胞和成熟的T细胞。CD6在转基因小鼠中的过度表达被认为会导致胸腺细胞和成熟淋巴细胞的表型和功能的改变。这一应用的重点是确定CD6在胸腺细胞选择和成熟T细胞的抗原反应中的功能。我们的具体目标是：1)鉴定我们新的表达人CD6并过表达总CD6的转基因小鼠的表型；2)测试在胸腺中依赖CD6的共刺激增加胸腺细胞选择的假设；3)测试在外周依赖CD6的共同刺激成熟T细胞微调其对特定抗原的反应的假设。CD6的表达可能通过增加对自身反应性胸腺细胞的选择，增加对凋亡和/或自然T细胞的抵抗力，以及降低成熟T细胞对自身抗原的刺激阈值，从而促进自身免疫。为了确定CD6的功能(S)，我们将使用互补的“功能获得”和“功能丧失”方法，包括培育出缺乏或过度表达CD6的小鼠，结合抗原特异性TCR转基因小鼠，胸腺器官培养，以及抑制CD6/CD6配体相互作用的特定可溶性试剂。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与较弱的自身抗原的反应，而不会影响对较强的外源抗原的反应，而较强的外源抗原在先天免疫中是重要的。

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.