Regulation of T cell activation and tolerance by Grail

摘要 T淋巴细胞的激活受到严格控制，以确保有效地消除入侵 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，特别是正、负共刺激 抗原呈递细胞上的分子，另一方面，也通过微妙的 细胞内信号转换器和调节器。最近，我们发现T细胞被激活 在没有CD28和ICOS的情况下，共刺激作用变得不起作用 无反应，支持共刺激在T细胞激活中的关键作用。这些 耐受性T细胞不仅无能，而且在TCR信号转导方面存在严重缺陷 但也完全缺乏效应器特异性转录因子的表达。 有趣的是，Grail(与淋巴细胞无能相关的基因)的表达仅 当CD28和ICOS信号同时缺失时，T细胞表达上调。圣杯是一款E3 泛素连接酶的表达与CD4T细胞相关 体外和体内无能。阻断负的共刺激信号(B7S1、B7-H3或 PD-1)恢复了T细胞功能，与效应器特异性表达相关 转录因子与GRAIL表达下调。确定功能的步骤 针对GRAIL在T细胞活化和耐受方面的研究，我们建立了GRAIL突变小鼠模型。 我们发现Grail缺陷的T细胞不依赖于CD28和ICOS信号。 体外激活和效应器分化。我们对当前研究的中心假设 圣杯分子对T细胞的耐受性和功能起着关键的调节作用。我们将首先 分析GRAIL在外周T细胞耐受中的作用。此外，我们将确定 GRAIL调节T细胞耐受的机制。其次，我们将分析 圣杯在自然和可诱导的Treg细胞生成和功能中的作用。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NAVE和/或Treg细胞缺陷引起。这些建议 研究将极大地提高我们对外周耐受和免疫功能的了解。 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.