Regulation of T cell activation and tolerance by Grail

Grail 对 T 细胞活化和耐受的调节

• 批准号: 7869435
• 负责人: Roza Insafetdinovna Nurieva
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869435
• 关键词: Antigen-Presenting Cells; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; CD28 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Defect; Development; Down-Regulation; Ensure; Generations; Genes; Hand; In Vitro; Interleukin-17; Invaded; Knockout Mice; Knowledge; Lead; Lymphocyte; Lymphocyte Activation; Modeling; Peripheral; Predisposition; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; T cell anergy; T cell regulation; T-Cell Activation; T-Lymphocyte; Tissues; Transducers; X Chromosome; abstracting; anergy; extracellular; immune function; immune self tolerance; in vivo; insight; mutant mouse model; novel; pathogen; peripheral tolerance; public health relevance; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Abstract T lymphocyte activation is tightly regulated to ensure effective elimination of invading pathogens as well as maintaining tolerance against self-tissues. On one hand, T cells are regulated by extracellular signals, especially the positive and negative costimulatory molecules on antigen-presenting cells, and on the other hand, also by delicate intracellular signal transducers and regulators. Recently, we found that T cells activated in the absence of both CD28 and ICOS costimulation became nonfunctional and nonresponsive, supporting a critical role of costimulation in T cell activation. These tolerant T cells not only were anergic with profound defects in TCR signal transduction but also completely lacked expression of effector-specific transcription factors. Interestingly, expression of Grail (gene related to anergy in lymphocytes), was only upregulated in T cells when both CD28 and ICOS signaling were absent. Grail is an E3 ubiquitin ligase whose expression was previously found to be associated with CD4 T cell anergy in vitro and in vivo. Blocking of negative costimulatory signals (B7S1, B7-H3 or PD-1) restored T cell function, associated with expression of effector-specific transcription factors and down-regulation of Grail expression. To determine the function of Grail in T cell activation and tolerance, we developed a Grail mutant mouse model. We found that Grail-deficient T cells were not dependent on CD28 and ICOS signaling in activation and effector differentiation in vitro. Our central hypothesis for the current study is that Grail molecule critically regulates T cell tolerance and function. We will first analyze the role of Grail in peripheral T cell tolerance. In addition, we will determine the mechanisms whereby Grail regulates T cell tolerance. Secondly, we will analyze the function of Grail in generation and function of natural and inducible Treg cells. Lastly, we will assess whether Grail deficiency will lead to susceptibility to autoimmune diseases and whether this is caused by defects in na¿ve and/or Treg cells. These proposed studies will greatly advance our knowledge on Grail function in peripheral tolerance and autoimmune responses. PUBLIC HEALTH RELEVANCE: T lymphocyte activation is tightly regulated to ensure effective elimination of invading pathogens as well as maintaining tolerance against self-tissues. On one hand, T cells are regulated by extracellular signals, especially the positive and negative costimulatory molecules on antigen-presenting cells, and on the other hand, also by delicate intracellular signal transducers and regulators. Our preliminary analysis of a Grail knockout mouse revealed its essential function in induction of T cell tolerance in vitro. In this project, we propose to continue our analysis on function of Grail in T cells in vitro and in vivo. These proposed studies will greatly advance our knowledge on Grail function in T cells and will provide a novel and unique insight into proper T cell regulation that governs self tolerance and immune function.

描述（由适用提供）：严格调节抽象的T淋巴细胞激活，以确保有效消除入侵的病原体，并保持对自我组织的容忍度。一方面，T细胞受细胞外信号的调节，尤其是抗原呈递细胞上的阳性和负共刺激分子，另一方面，也是由精致的细胞内信号传感器和调节剂的调节。最近，我们发现在没有CD28和ICOS共刺激的情况下激活的T细胞变得无功能且无反应，从而支持共刺激在T细胞激活中的关键作用。这些耐受性T细胞不仅是厌食症，在TCR信号转导中具有深远的缺陷，而且完全缺乏效应特异性转录因子的表达。有趣的是，在没有CD28和ICOS信号传导的情况下，Grail的表达（与淋巴细胞中的基因相关）仅在T细胞中进行更新。 Grail是一种E3泛素连接酶，以前发现其表达与CD4 T细胞在体外和体内有关。负面刺激信号（B7S1，B7-H3或PD-1）的阻断恢复了T细胞功能，与效应特异性转录因子的表达相关，并下调了Grail表达。为了确定GRAIL在T细胞激活和耐受性中的功能，我们开发了一种Grail突变小鼠模型。我们发现，缺乏圣母的T细胞在体外激活和效应子分化中不依赖CD28和ICOS信号传导。我们目前研究的中心假设是，圣杯分子严格调节T细胞的耐受性和功能。我们将首先分析圣杯在外周T细胞耐受性中的作用。此外，我们将确定圣杯调节T细胞耐受性的机制。其次，我们将分析圣杯在天然和诱导的Treg细胞的生成和功能中的功能。最后，我们将评估圣杯缺乏症是否会导致对自身免疫性疾病的敏感性，以及这是否是由NA¿VE和/或Treg细胞缺陷引起的。这些拟议的研究将大大提高我们在外围耐受性和自身免疫反应中的圣杯功能的知识。 公共卫生相关性：严格调节T淋巴细胞的激活，以确保有效消除入侵的病原体以及保持对自我组织的宽容。一方面，T细胞受细胞外信号的调节，尤其是抗原呈递细胞上的阳性和负共刺激分子，另一方面，也是由精致的细胞内信号传感器和调节剂的调节。我们对小鼠小鼠的初步分析显示了其体外T细胞耐受性的基本功能。在这个项目中，我们建议继续我们对体外和体内T细胞中Grail功能的功能的分析。这些提出的研究将大大提高我们对T细胞中圣杯功能的知识，并将为控制自耐力和免疫学功能的适当T细胞调节提供新颖而独特的见解。