Control of T cell tolerance and regulation through NFAT complex formation

通过 NFAT 复合物形成控制 T 细胞耐受和调节

• 批准号: 46137870
• 负责人: Professor Dr. Vigo Heissmeyer
• 金额: --
• 依托单位: Forschungsbereich Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/46137870?language=en
• 关键词: Control; cell; tolerance; regulation; through

The investigation of molecular mechanisms of immune tolerance should lead to the development of specific therapies for autoimmune diseases. T cells play a central role in the etiology of many autoimmune diseases. Signaling through the T cell receptor leads to activation of the transcription factor Nuclear Factor of Activated T cells (NFAT). The underlying hypothesis of this proposal is as follows: The decision whether a T cell commits to productive activation or, alternatively, enters a tolerance program is made by NFAT complex formation with different interaction partners. Accordingly, experimental manipulation of interaction partner availability is expected to change the transcriptional program and thereby the cellular phenotype. In order to test this hypothesis, we will manipulate different transcriptional programs and evaluate the impact on T cell responses. We will induce NFAT dependent, activation protein 1 (AP-1) independent transcription and determine whether this is sufficient to induce a state of adaptive tolerance in T cells. As a second focus, we will expand on our recent finding that Forkhead box P3 (Foxp3) can bind with NFAT on composite NFAT/AP-1 sites, forming a complex that is required for regulatory T cell (Treg) function. We will determine whether NFAT/Foxp3 complex formation is required for Treg development or functions during Treg-mediated bystander suppression. As a possible therapeutic avenue, we will determine whether co-expression of constitutively active NFAT together with Foxp3 can induce a stable regulatory T cell phenotype. Finally, we will address whether complex formation with AP-1 antagonizes NFAT function in adaptive tolerance and regulatory T cell activity.

对免疫耐受分子机制的研究应有助于开发针对自身免疫性疾病的特异性疗法。T细胞在许多自身免疫性疾病的病因学中起核心作用。通过T细胞受体的信号传导导致转录因子活化T细胞核因子（NFAT）的活化。该提议的基本假设如下：T细胞是否致力于生产性激活或替代地进入耐受程序的决定是通过与不同相互作用伴侣形成NFAT复合物来做出的。因此，预期相互作用伴侣可用性的实验操作会改变转录程序，从而改变细胞表型。为了验证这一假设，我们将操纵不同的转录程序，并评估对T细胞反应的影响。我们将诱导NFAT依赖性、激活蛋白1（AP-1）非依赖性转录，并确定这是否足以诱导T细胞中的适应性耐受状态。作为第二个重点，我们将扩展我们最近的发现，即叉头盒P3（Foxp 3）可以与复合NFAT/AP-1位点上的NFAT结合，形成调节性T细胞（Treg）功能所需的复合物。我们将确定NFAT/Foxp 3复合物的形成是否需要Treg的发展或功能在Treg介导的旁观者抑制。作为一种可能的治疗途径，我们将确定组成型活性NFAT与Foxp 3的共表达是否可以诱导稳定的调节性T细胞表型。最后，我们将讨论AP-1复合物的形成是否拮抗NFAT在适应性耐受和调节T细胞活性中的功能。