Regulation of peripheral T cell tolerance

描述（由申请人提供）：调节性T细胞（T细胞）的主动抑制和T细胞无反应性是外周T细胞耐受的两种重要机制。T细胞受体（TCR）信号传导对于Treg功能和T细胞无反应性的诱导至关重要。然而，TCR信号传导也可以在共刺激信号的存在下激活T细胞。如何调节TCR信号传导以指导这些不同的T细胞命运/功能还知之甚少。二酰基甘油（DAG）激酶（DGK）催化DAG通过磷酸化转化为磷脂酸。我们和其他人最近已经证明，DGK 1和6，在T细胞中表达的同种型，通过抑制TCR诱导的DAG-RasGRP 1-Ras-Erk 1/2-AP 1级联反应的激活来负控制T细胞活化。DGK 1或DGK 6的缺乏导致T细胞对TCR刺激反应过度，并赋予对无反应性诱导的一定抗性。我们对该应用的中心假设是DGK 1和6协同调节DAG代谢，并通过促进T细胞无反应性和Treg功能在T细胞自身耐受中发挥关键作用。在初步数据的有力支持下，我们计划通过追求三个具体目标来验证我们的假设。在目标1中，我们将确定DGK 1和6如何协同控制T细胞无反应性以获得自身耐受。我们将使用已经产生的DGK 1-/-6-/-小鼠以及正在产生的条件性DGK 16缺陷小鼠来测试DGK 1和6协同控制T细胞的内在特性以促进无反应性的假设。在目标2中，我们将研究DGK活性导致T细胞无能的机制。在目标3中，我们将阐明DGK活性调节Treg功能的机制。拟议的研究应显着提高对调节T细胞无能和Treg功能的机制的理解，并确定调节免疫应答以治疗自身免疫性疾病的策略。 公共卫生相关性：该项目旨在提高我们对控制T细胞无能和调节性T细胞（Treg）功能的分子机制的理解。我们预期建立和定义二酰基甘油激酶活性在T细胞无反应性、Treg功能和对肝脏的自身耐受中的重要作用。这项拨款提案中的研究还应该提供治疗靶点，以调节自身免疫性疾病的T细胞耐受性。

DESCRIPTION (provided by applicant): Active suppression by regulatory T cells (Tregs) and T cell anergy are two important mechanisms for peripheral T cell tolerance. T cell receptor (TCR) signaling is critical for Treg function and induction of T cell anergy. However, TCR signaling can also activate T cells in the presence of a costimulatory signal. How TCR signaling is regulated to direct these distinct T cell fates/functions has been poorly understood. Diacylglycerol (DAG) kinases (DGKs) catalyze the conversion of DAG to phosphatidic acid through phosphorylation. We and others have recently demonstrated that DGK1 and 6, isoforms expressed in T cells, negatively control T cell activation by inhibiting TCR-induced activation of the DAG-RasGRP1-Ras-Erk1/2-AP1 cascade. Deficiency of either DGK1 or 6 causes T cells to be hyperresponsive to TCR stimulation and confers certain resistance to anergy induction. Our central hypothesis for this application is that DGK1 and 6 synergistically regulate DAG metabolism and play a pivotal role in T cell self-tolerance by promoting T cell anergy and Treg function. With strong support from preliminary data, we plan to test our hypothesis by pursuing three specific aims. In aim 1, we will determine how DGK1 and 6 synergistically control T cell anergy for self-tolerance. We will use already generated DGK1-/-6-/- mice as well as conditional DGK16 deficient mice being generated to test the hypothesis that DGK1 and 6 synergistically control the intrinsic property of T cells to promote anergy. In aim 2, we will investigate mechanisms by which DGK activity contributes to T cell anergy. In aim 3, we will elucidate the mechanisms by which DGK activity regulates Treg function. The proposed studies should significantly improve understanding of the mechanisms that regulate T cell anergy and Treg function, and identify strategies for modulating immune responses in order to treat autoimmune diseases. PUBLIC HEALTH RELEVANCE: The project proposed in this grant application aims to improve our understanding of the molecular mechanisms that control T cell anergy and regulatory T cell (Treg) function. We anticipate establishing and defining an important role of diacylglycerol kinase activity in T cell anergy, Treg function and self-tolerance to the liver. Studies in this grant proposal should also provide therapeutic targets to regulate T cell tolerance for autoimmune diseases.