Control of T cell tolerance and regulation through NFAT complex formation

对免疫耐受分子机制的研究将促进自身免疫性疾病特异性治疗的发展。T细胞在许多自身免疫性疾病的病因学中起着核心作用。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）的激活。这一提议的基本假设如下：决定T细胞是进行生产激活还是进入耐受程序是由NFAT复合物与不同的相互作用伙伴形成的。因此，对相互作用伴侣可用性的实验操作有望改变转录程序，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、活化蛋白1 （AP-1）独立的转录，并确定这是否足以诱导T细胞的适应性耐受状态。作为第二个重点，我们将扩展我们最近的发现，叉头盒P3 （Foxp3）可以在复合NFAT/AP-1位点上与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/Foxp3复合物的形成是否需要Treg发育或在Treg介导的旁观者抑制中发挥作用。作为一种可能的治疗途径，我们将确定组成活性NFAT与Foxp3的共表达是否可以诱导稳定的调节性T细胞表型。最后，我们将探讨AP-1复合物的形成是否会在适应性耐受性和调节性T细胞活性中拮抗NFAT功能。

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.