Regulation of T cell activation and tolerance by Grail

摘要 T淋巴细胞活化受到严格调节，以确保有效清除入侵的细胞。 病原体以及保持对自身组织的耐受性。一方面，T细胞 受细胞外信号的调节，尤其是正性和负性共刺激信号。 另一方面，也可以通过精细的 细胞内信号转导和调节器。最近，我们发现T细胞激活 在缺乏CD28和ICOS的情况下，共刺激变得无功能， 无应答，支持共刺激在T细胞活化中的关键作用。这些 耐受性T细胞不仅无反应性，而且在TCR信号转导中存在严重缺陷 而且完全缺乏效应子特异性转录因子的表达。 有趣的是，Grail（淋巴细胞中与无反应性相关的基因）的表达仅在 当CD28和ICOS信号传导都不存在时，在T细胞中上调。圣杯是E3 先前发现其表达与CD4 T细胞相关的泛素连接酶 体外和体内无反应性。阻断负共刺激信号（B7 S1、B7-H3或B7-H4） PD-1）恢复T细胞功能，与效应子特异性 转录因子和下调Grail表达。来确定函数 为了研究Grail在T细胞活化和耐受中的作用，我们建立了Grail突变小鼠模型。 我们发现Grail缺陷型T细胞在免疫应答中不依赖于CD28和ICOS信号。 体外激活和效应物分化。我们当前研究的中心假设 Grail分子严格调节T细胞耐受性和功能。我们将首先 分析Grail在外周血T细胞耐受中的作用。此外，我们将确定 Grail调节T细胞耐受性的机制。其次，我们将分析 Grail在天然和诱导型Treg细胞的产生和功能中的功能。最后我们 将评估圣杯缺乏是否会导致自身免疫性疾病的易感性 以及这是否由幼稚细胞和/或Treg细胞的缺陷引起。这些拟议 这些研究将极大地推进我们对Grail在外周耐受中的功能的认识， 自身免疫反应

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.