Hippo signaling in stable regulatory activity and immune tolerance

程序描述/摘要 外周免疫耐受的核心成分是Foxp3[+]调节性T细胞(Tregs)。Treg对于预防自身免疫性疾病是不可或缺的，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STAT5信号来控制Treg的动态平衡和最近的谱系稳定性的主要调节因子。最近的研究还发现了一个高度抑制的p-STAT5[+]Treg亚群，它对抑制自身反应性T细胞和早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特异性地激活Tregs来改善自身免疫性疾病，人们对探索这一新的治疗策略越来越感兴趣。与传统T细胞不同，Tregs通常处于部分IL-2缺乏的状态，部分原因是Foxp3依赖于抑制IL-2的产生，因此被索引为低IL-2信号阈值。此外，由于Tregs在IL-2R下游的PI3K和MAPK活性较低，因此对STAT5活性的需求占主导地位。Treg特异性调节IL-2和STAT5信号的机制仍不清楚。通过激酶抑制剂筛选，我们确定Mst1是河马信号中的一个核心激酶，是一种新的IL-2信号传感器，可以放大Tregs中的STAT5激活，而不是传统的T细胞。因此，我们假设河马蛋白激酶选择性地感知和放大IL-2R Treg STAT5信号，使−适应合适的IL-2信号阈值，从而维持稳定的Treg群体和调节活性。目的1.在体内动态平衡和激活状态下，建立Tregs内Mst1-−-STAT5轴。目的2.河马/Mst1在Tregs中是如何发出信号的？目的3.定义和重建Tregs中依赖IL-2的信号通路。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，以及河马信号的新机制，有可能转化为针对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.