Role of Notch 1 in Immune Tolerance

描述（由申请人提供）：对T细胞活化的理解的最新进展导致了治疗免疫性疾病的新治疗方法。一个有吸引力的干预靶点是阻断T细胞介导的共刺激途径，这导致仅对那些遇到特异性抗原的T细胞产生更多的选择性作用。事实上，在某些情况下，CD 28/B7共刺激途径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的进展。然而，许多其他细胞表面分子存在于初始T细胞上，其可能在从静止状态启动免疫中起重要作用。此外，很明显，静止T细胞也可以作为调节性T细胞发挥作用，以促进免疫耐受，其机制尚不清楚，这表明一些细胞表面蛋白可能提供功能活性，而不仅仅是确定细胞是否有效地进入细胞周期。Notch、Serrate和Delta是1型整合膜蛋白，参与对正常细胞分化和器官发生至关重要的细胞-细胞信号传导。在免疫系统中，Notch信号传导对于正常T细胞发育至关重要。最近，Notch信号传导在成熟T细胞中的作用已经基于以下观察而被提出：Notch通过锯齿的接合可以在体内诱导外周T细胞中的无反应性的深刻状态。最有趣的是观察到这些“无反应”T细胞具有调节能力，在几个水平上似乎类似于能够调节自身免疫的CD 25+调节细胞。我们的初步研究表明，Notch-1是静息T细胞中T细胞信号传导的重要调节因子，并可能参与耐受。我们假设Notch-1通过影响激活幼稚T细胞的主要信号通路在T细胞应答的内在调节中起关键作用。这导致T细胞失活或分化改变。此外，我们假设通过Notch-1操纵免疫应答可用于改变自身免疫和移植耐受。在本申请中，我们提出探索T细胞中Notch信号传导的机制及其应用，如下所示：确定T细胞中Notch信号传导的生物化学、细胞和遗传效应;和具体目标#2。Notch信号传导在建立外周T细胞耐受中的体内应用。

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.