Role of Notch 1 in Immune Tolerance

描述(由申请人提供)：在理解T细胞激活方面的最新进展导致了治疗免疫疾病的新的治疗方法。干预的一个有吸引力的目标是阻断T细胞介导的共刺激通路，这导致只对那些遇到特定抗原的T细胞产生更多的选择性效应。事实上，在某些情况下，CD28/B7共刺激通路拮抗剂可以诱导抗原特异性耐受，从而防止自身免疫性疾病和器官移植排斥反应的进展。然而，幼稚T细胞上存在许多其他细胞表面分子，它们可能在启动静止状态的免疫中发挥重要作用。此外，很明显，静止的T细胞也可以作为调节性T细胞来促进免疫耐受，其机制尚不清楚，表明一些细胞表面蛋白可能提供功能活动，而不仅仅是决定细胞是否有效地进入细胞周期。Noch、Serrate和Delta是参与细胞-细胞信号转导的1型整合膜蛋白，对正常细胞分化和器官发生至关重要。在免疫系统中，Notch信号对T细胞的正常发育至关重要。最近，基于观察到Serrate与Notch的接触可以在体内诱导外周T细胞处于严重的无反应状态，有人提出了Notch信号在成熟T细胞中的作用。最有趣的是观察到，这些“无反应”的T细胞具有在几个层面上看起来类似于能够调节自身免疫的CD25+调节细胞的调节能力。我们的初步研究表明，Notch-1是静息T细胞中T细胞信号的重要调节因子，可能与耐受有关。我们假设Notch-1通过影响对激活初始T细胞至关重要的主要信号通路，在T细胞反应的内在调节中发挥关键作用。这会导致T细胞失活或分化改变。此外，我们假设通过Notch-1对免疫反应的操纵可以用于改变自身免疫和移植耐受。在这一应用中，我们建议探索T细胞中Notch信号的机制及其应用如下：特殊目的1.鉴定Notch信号在T细胞中的生化、细胞和遗传效应；特殊目的2.体内应用Notch信号建立外周T细胞耐受。

DESCRIPTION (provided by applicant): Recent advances in the understanding of T-cell activation have led to new therapeutic approaches in the treatment of immunological disorders. One attractive target of intervention has been the blockade of T cell-mediated co-stimulatory pathways, which result in more selective effects on only those T-cells that have encountered specific antigen. In fact, in some instances, CD28/B7 co-stimulatory pathway antagonists can induce antigen-specific tolerance that prevents the progression of autoimmune diseases and organ graft rejection. However, many other cell surface molecules exist on naive T cells that may play an important role in initiating immunity from the quiescent state. Moreover, it is clear that quiescent T cells can also function as regulatory T cells to promote immune tolerance by an as yet unknown mechanism suggesting that some of the cell surface proteins may provide functional activities beyond just determining whether cells effectively go into cell cycle. Notch, Serrate, and Delta are type 1 integral membrane proteins involved in cell-cell signaling crucial to normal cellular differentiation and in organogenesis. In the immune system, Notch signaling is critical for normal T cell development. Recently, a role for Notch signaling in mature T cells has been proposed based on the observation that engagement of Notch by Serrate could induce a profound state of unresponsiveness in peripheral T cells in vivo. Most interesting was the observation that these "unresponsive" T cells possessed regulatory abilities that on several levels appear similar to the CD25+ regulatory cells that are able to regulate autoimmunity. Our preliminary studies suggest that Notch-1 is an important regulator of T cell signaling in resting T cells and may be involved in tolerance. We hypothesize that Notch-1 plays a critical role in the intrinsic regulation of T cell responses by influencing the primary signaling pathways critical for activating naive T cells. This results in T cell inactivation or altered differentiation. Moreover, we hypothesize that manipulation of immune responses through Notch-1 can be used to alter autoimmunity and transplantation tolerance. In this application we propose to explore the mechanisms of Notch signaling in T cells and its application as follows: Specific Aim #1. To Identify the biochemical, cellular and genetic effects of Notch signaling in T cells; and Specific Aim #2. In vivo application of Notch signaling for the establishment of peripheral T cell tolerance.