Control of dysfunctional Tregs

项目摘要 排斥反应仍然是移植肾长期存活的主要障碍，我们渴望揭开 阻碍同种异体移植物稳定存活的基本机制。在上一个资助期，我们研究了 Treg功能障碍的机制及BATF和BATF3是Foxp3的有效抑制因子， 抑制Foxp3的表达和Treg的诱导。这些研究还导致了DHX15的发现 解旋酶作为Foxp3Tregs的关键调节因子，因为Tregs中Dhx15的条件缺失导致了 外周Tregs的严重枯竭和致命性自身免疫性疾病。从本质上讲，DHX15是一种 RNA解旋酶(一种与RNA结合的马达蛋白)，传统上被认为与RNA加工有关。它的 在Tregs的控制中的角色是意想不到的，并清楚地揭示了Tregs以前不为人知的新方面 不同于目前已知的机制，而发现这些机制是中心目标 这项提议。 我们的工作假设是DHX15控制着Treg的身份和/或周围部位的存活，而且它的 缺乏会导致它们回复到TJeff或死于细胞凋亡。我们推测DHX15也可能 控制移植物部位的Tregs，它们必须克服炎症环境才能发挥抑制作用 功能。我们在这个应用中提出了3个目标来检验这一假设：第一个目标是检验 DHX15通过作为RNA剪接因子来控制Treg的身份，处理编码 Foxp3或Foxp3控制Treg中的签名分子，第二个目标是解决DHX15 通过调节IL-2信号复合体来控制Tregs的存活，使Tregs在其 第三个目的是检查DHX15是否对移植物部位的Treg特别重要 在促进移植耐受方面最需要它们的地方。总之，DHX15是第一个RNA解旋酶 到目前为止已确定的控制Tregs、转基因模型以及尖端技术的 我们开发的方法使我们处于一个独特的位置，可以机械地剖析DHX15 解旋酶在调节Treg中起作用，这在基础Treg生物学和Treg生物学中都是相当重要的领域。 以治疗为基础。

Project Summary Rejection remains a major hurdle to long lasting transplant survival and we aspire to uncover the fundamental mechanisms that hinder stable allograft survival. In the last funding period, we studied the mechanisms of Treg dysfunctions and identified BATF and BATF3 as potent repressors of Foxp3, suppressing Foxp3 expression and Treg induction. These studies also led to the discovery of the DHX15 helicase as a critical regulator of Foxp3+Tregs, as conditional deletion of Dhx15 in Tregs resulted in a profound depletion of Tregs in the periphery and lethal autoimmune diseases. In essence, DHX15 is an RNA helicase (an RNA binding motor protein) and traditionally thought to be involved in RNA processing. Its roles in the control of Tregs are unexpected and clearly reveal novel previously unknown aspects of Tregs that are different from currently known mechanisms, and uncovering those mechanisms is the central goal of this proposal. Our working hypothesis is that DHX15 controls Treg identity and/or survival at peripheral sites and that its deficiency results in either their reversion to Teff or die of apoptosis. We surmise that DHX15 may also control Tregs at the graft site, where they must overcome the inflammatory milieu to exert suppressive functions. We proposed 3 Aims to test this hypothesis in this application: the first Aim is to test whether DHX15 controls Treg identity by acting as an RNA splicing factor, processing mRNAs that encode the Foxp3 or Foxp3 controlled signature molecules in Tregs, the second Aim is to address whether DHX15 controls Tregs survival by regulating the IL-2 signaling complex, such that Tregs die of apoptosis in its absence, and the third Aim is to examine whether DHX15 is especially important for Tregs at graft sites where they are needed the most in promoting transplant tolerance. Overall, DHX15 is the first RNA helicase identified thus far that controls Tregs, and the genetically modified models as well as cutting-edge approaches we have developed put us in a unique position in dissecting mechanistically how the DHX15 helicase acts in regulating Tregs, an area of considerable importance in both basic Treg biology and Treg- based therapies.