Hippo signaling in stable regulatory activity and immune tolerance

项目描述/摘要 外周免疫耐受的中心组分是Foxp 3 [+]调节性T细胞（Tcells）。免疫球蛋白是预防自身免疫性疾病不可或缺的，但也是肿瘤免疫和免疫治疗的主要障碍。IL-2被认为是通过STAT 5信号传导控制TcB的稳态和最近的谱系稳定性的主要调节剂。最近的研究还发现了高度抑制性p-STAT 5 [+] Treg亚群，其对于抑制自身反应性T细胞和初期自身免疫至关重要。值得注意的是，在小鼠模型和临床试验中，低剂量的IL-2特异性激活TcB以改善自身免疫性疾病，并且人们对探索这种新的治疗策略越来越感兴趣。与传统的T细胞不同，TcB通常保持在部分IL-2缺乏的状态，部分原因是Foxp 3依赖性抑制IL-2的产生，因此被指示为低IL-2信号传导阈值。此外，由于它们在IL-2 R下游的低PI 3 K和MAPK活性，TcB显示出对STAT 5活性的主要需求。Treg特异性调节IL-2和STAT 5信号传导的机制仍不确定。通过激酶抑制剂筛选，我们确定了Mst 1，一种Hippo信号传导中的核心激酶，作为一种新型的IL-2信号传感器，可以放大TcM中的STAT 5激活，而不是传统的T细胞。因此，我们假设Hippo激酶选择性地感知和放大IL-2 R-STAT 5信号，以使TclG适应适当的IL-2信号阈值，从而维持稳定的Treg群体和调节活性。目标1。在体内稳态和激活状态下建立Tcells中的Mst 1 − STAT 5轴。目标二。Hippo/Mst 1在Tibet中如何发出信号？目标3：定义和重建THEX中的IL-2依赖性信号通路。我们预测我们的研究将在Treg生物学和免疫调节方面建立一个新的范式，以及Hippo信号传导的新机制，并有可能转化为靶向自身免疫和癌症的创新策略。

Program Description/Abstract A central component of peripheral immune tolerance is Foxp3[+] regulatory T cells (Tregs). Tregs are indispensable for the prevention of autoimmune diseases, but also serve as a major hurdle to tumor immunity and immunotherapy. IL-2 is considered a major regulator for controlling the homeostasis and more recently, lineage stability, of Tregs by signaling through STAT5. Recent studies have also discovered a highly suppressive p-STAT5[+] Treg subpopulation that is critical for the suppression of autoreactive T cells and incipient autoimmunity. Of note, low-dose IL-2 specifically activates Tregs to ameliorate autoimmune diseases in murine models and clinical trials, and there is a growing interest in exploring this new therapeutic strategy. Unlike conventional T cells, Tregs are normally kept in a state of partial IL-2 deficiency due to, in part, Foxp3-dependent repression of IL-2 production and are therefore indexed to a low IL-2 signaling threshold. Additionally, Tregs show a predominant requirement of STAT5 activity due to their low PI3K and MAPK activities downstream of IL-2R. Mechanisms underlying Treg-specific regulation of IL-2 and STAT5 signaling remain uncertain. Through a kinase inhibitor screen, we identified Mst1, a core kinase in Hippo signaling, as a novel IL-2 signal sensor to amplify STAT5 activation in Tregs but not conventional T cells. We therefore hypothesize that Hippo kinases selectively sense and amplify IL-2R−STAT5 signaling to adapt Tregs to a proper IL-2 signaling threshold, thereby maintaining a stable Treg population and regulatory activity. Aim 1. Establish Mst1−STAT5 axis in Tregs under homeostasis and activation in vivo. Aim 2. How does Hippo/Mst1 signal in Tregs? Aim 3. Define and reconstruct IL-2-dependent signaling circuits in Tregs. We predict our studies will establish a new paradigm in Treg biology and immune regulation, as well as new mechanisms of Hippo signaling, with the potential to translate into innovative strategies to target autoimmunity and cancer.