Hippo signaling in stable regulatory activity and immune tolerance

Hippo 信号传导稳定的调节活性和免疫耐受

基本信息

批准号：
10189499
负责人：
Hongbo Chi
金额：
$ 44.88万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189499
关键词：
Affinity Chromatography Alleles Amplifiers Autoimmune Autoimmune Diseases Autoimmunity Biological Assay Biology Cell Respiration Cells Clinical Trials Complex Cytometry Cytoskeletal Modeling Dependence Development Disease Dose FOXP3 gene Family Guanosine Triphosphate Phosphohydrolases Homeostasis Immune Immune Tolerance Immune response Immunologics Inflammatory Interleukin-2 JAK3 gene Knock-in MAP Kinase Gene Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Pathway Mitochondrial Proteins Molecular Mus Pathway interactions Peripheral Phosphotransferases Population Prevention Production Program Description Proteins Proteomics Reading Frames Regulation Regulatory T-Lymphocyte Repression Resistance Role Shapes Signal Transduction Stat5 protein Symptoms Systems Biology T-Lymphocyte Techniques Testing Translating Tumor Immunity autoreactive T cell experimental study fitness immunoregulation in vivo indexing innovation innovative technologies interest kinase inhibitor mitochondrial metabolism mouse model neoplasm immunotherapy novel novel therapeutic intervention phosphoproteomics prevent rho sensor tumor tumor microenvironment

项目摘要

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.

程序说明/摘要外周免疫耐受性的一个核心成分是FOXP3 [+]调节性T细胞（Tregs）。 Tregs对于预防自身免疫性疾病是必不可少的，但也是肿瘤免疫疗法和免疫疗法的主要障碍。 IL-2被认为是控制体内稳态的主要调节剂，最近通过STAT5发出信号传导Treg的谱系稳定性。最近的研究还发现了高度抑制的P-Stat5 [+] Treg亚群，这对于抑制自动反应性T细胞和初期自身免疫至关重要。值得注意的是，低剂量IL-2专门激活Treg，以改善鼠模型和临床试验中的自身免疫性疾病，并且对探索这种新理论策略的兴趣越来越浓厚。与常规的T细胞不同，Treg通常由于IL-2产生的FOXP3依赖性表示，因此将Treg保持在局部IL-2缺陷状态，因此被索引为低IL-2信号传导阈值。此外，由于IL-2R下游的PI3K低和MAPK活动，Tregs对STAT5活性的主要要求。 IL-2和STAT5信号传导的Treg特异性调节的机制仍然不确定。通过激酶抑制剂筛选，我们确定了MST1（河马信号传导中的核心激酶）为一种新型的IL-2信号传感器，以扩增Treg中的STAT5激活，但不能扩增常规T细胞。因此，我们假设河马/MST1信号传导使Treg适应了适当的IL-2信号传导阈值，从而保持了稳定的Treg人群和调节活性。 AIM 1。在体内稳态下建立MST1-Stat5轴，并在体内激活。 AIM2。Treg中的河马/MST1信号如何？ AIM 3。定义并重建Treg中的IL-2依赖性信号电路。我们预测，我们的研究将建立Treg生物学和免疫调节的新范式，以及河马信号传导的新机制，并有可能转化为靶向自身免疫性和癌症的创新策略。