Control of T cell tolerance and regulation through NFAT complex formation

对免疫耐受分子机制的研究将有助于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中起着核心作用。信号通过T细胞受体导致转录因子活化T细胞核因子(NFAT)。这一建议的基本假设如下：T细胞是否致力于生产性激活或进入耐受计划的决定是由NFAT复合体与不同的相互作用伙伴形成的。因此，对相互作用伙伴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依赖的激活蛋白1(AP-1)非依赖的转录，并确定这是否足以在T细胞中诱导适应性耐受状态。作为第二个焦点，我们将扩展我们最近的发现，Forkhead box P3(Foxp3)可以与NFAT/AP-1复合位点上的NFAT结合，形成调节T细胞(Treg)功能所需的复合体。我们将确定在Treg介导的旁观者抑制过程中，是否需要形成NFAT/Foxp3复合体来实现Treg的发育或功能。作为一种可能的治疗途径，我们将确定结构性活性NFAT与Foxp3的共同表达是否能够诱导稳定的调节性T细胞表型。最后，我们将讨论与AP-1形成的复合体是否拮抗NFAT在适应性耐受和调节T细胞活动中的功能。

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.