The role of Notch signaling in T cell function

描述（由申请人提供）：Notch蛋白家族由四种高度保守的膜受体组成。这些蛋白质中的至少三种，Notch 1、Notch 2和Notch 3，在淋巴发育期间的不同时间表达。在正常情况下，Notch表达指导T细胞谱系的发育。Notch异常表达导致T淋巴肿瘤，表明该基因的表达可参与致癌转化。本提案中提供的初步数据表明，通过T细胞受体（TCR）的信号传导诱导Notch依赖性信号传导途径的表达和激活。为了确定外周T细胞中TCR诱导的Notch表达的结果，检查了表达反义Notch构建体（Notch AS）的小鼠。另外，使用Notch活化的药理学抑制剂来抑制Notch活性。使用这两种方法，提供的数据表明，Notch活化是TCR诱导的T细胞的CD 4和CD 8亚群增殖所必需的。根据我们的初步数据，我们假设外周T细胞中的Notch信号传导具有几个重要的后果。首先，在CD 4和CD 8 T细胞中，Notch信号传导驱动细胞因子产生和增殖。我们还提出了通过TCR调节Notch表达并导致NF-κ B活化的特异性信号通路。我们提出Notch是CD 8 T细胞中NF-kB活性和IFN-γ产生所必需的，并表明NF-kB可能直接调节CD 8细胞中IFN-γ的产生。我们还提出，Notch是所需的Th 1功能，无论是参与极化的幼稚CD 4细胞到Th 1或驱动Th 1细胞因子的生产极化后。我们的数据还支持CD 4+，CD 25-亚群与CD 4+，CD 25+亚群中差异Notch活化的作用，并表明这些重要的CD 4 T细胞亚群中的Notch表达可能具有功能性后果。最后，我们提出Notch可能通过激活cyclin D2和D3来调节T细胞的细胞周期进程。提出了四个目标来解决提出的假设。目的探讨TCR信号通路如何调节Notch的激活。目的II询问Notch如何调节NF-κ B。目的III检查外周T细胞中Notch激活的功能后果，目的IV询问Notch如何调节T细胞中的细胞周期进程。

DESCRIPTION (provided by applicant): The Notch family of proteins is comprised of four highly conserved membrane receptors. At least three of these proteins, Notch1, Notch2 and Notch3, are expressed at various times during lymphoid development. Under normal circumstances, Notch expression directs the development of the T cell lineage. Aberrant Notch expression results in T lymphoid tumors suggesting the expression of this gene can participate in oncogenic transformation. Preliminary data presented in this proposal demonstrate that signaling via the T cell receptor (TCR) induces both the expression and activation of a Notch-dependent signaling pathway. To determine the consequences of TCR-induced Notch expression in peripheral T cells, mice expressing an antisense Notch construct (Notch AS) were examined. Additionally pharmacological inhibitors of Notch activation were used to inhibit Notch activity. Using these two approaches, data is presented demonstrating that Notch activation is required for TCR-induced proliferation of both CD4 and CD8 subsets of T cells. From our preliminary data, we hypothesize that Notch signaling in peripheral T cells has several important consequences. First of all, in both CD4 and CD8 T cells, Notch signaling drives cytokine production and proliferation. We also suggest a specific signaling pathway through the TCR that regulates Notch expression and results in activation of NF-kB. We propose that Notch is required for both NF-kB activity and IFN-gamma production in CD8 T cells and suggest that NF-kB may directly regulate IFN-gamma production in CD8 cells. We also propose that Notch is required for Th1 function either by participating in the polarization of naive CD4 cells into Th1 or by driving Th1 cytokine production following polarization. Our data also support a role for differential Notch activation in the CD4+, CD25- subset versus the CD4+, CD25+ subset and suggest that Notch expression in these important CD4 T cell subsets may have functional consequences. Lastly we propose that Notch may regulate cell cycle progression in T cells through activation of cyclin D2 and D3. Four aims are proposed to address the hypotheses presented. Aim I asks how TCR signaling regulates Notch activation. Aim II asks how Notch regulates NF-kB. Aim III examines the functional consequences of Notch activation in peripheral T cells and Aim IV asks how Notch regulates cell cycle progression in T cells.