Regulation of peripheral T cell tolerance

描述（由申请人提供）：调节性T细胞（Tregs）的主动抑制和T细胞能量是外周T细胞耐受的两个重要机制。T细胞受体（TCR）信号是Treg功能和诱导T细胞能量的关键。然而，TCR信号也可以在共刺激信号存在的情况下激活T细胞。如何调节TCR信号来指导这些不同的T细胞命运/功能，目前还知之甚少。二酰基甘油（DAG）激酶（DGKs）通过磷酸化催化DAG转化为磷脂酸。我们和其他人最近已经证明，在T细胞中表达的DGK1和6亚型，通过抑制tcr诱导的DAG-RasGRP1-Ras-Erk1/2-AP1级联的激活，负性地控制T细胞的激活。DGK1或dg6的缺乏会导致T细胞对TCR刺激产生高反应，并对能量诱导产生一定的抵抗力。我们的核心假设是DGK1和6协同调节DAG代谢，并通过促进T细胞能量和Treg功能在T细胞自我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。在目的1中，我们将确定DGK1和6如何协同控制T细胞能量以实现自我耐受。我们将使用已经生成的DGK1-/-6-/-小鼠以及正在生成的条件DGK16缺陷小鼠来验证DGK1和6协同控制T细胞的内在特性以促进能量的假设。在目标2中，我们将研究DGK活性促进T细胞能量的机制。在目标3中，我们将阐明DGK活性调节Treg功能的机制。拟议的研究将显著提高对调节T细胞能量和Treg功能的机制的理解，并确定调节免疫反应的策略，以治疗自身免疫性疾病。

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.