Regulating peripheral T cell tolerance

调节外周 T 细胞耐受性

• 批准号: 9180049
• 负责人: XIAOPING ZHONG
• 金额: $ 39.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180049
• 关键词: Autoimmune Diseases; CD8-Positive T-Lymphocytes; CDK4 gene; Cancer Patient; Cell physiology; Cells; Chimeric Proteins; Consumption; Data; Development; Diacylglycerol Kinase; Diglycerides; Ensure; Enzymes; FRAP1 gene; Goals; Health; Homeostasis; Immune response; Individual; Interleukin 7 Receptor; Knowledge; Lead; Lipids; Maintenance; Major Histocompatibility Complex; Mammals; Metabolic stress; Modeling; Mouse Strains; Mus; Mutation; Nutrient; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Phosphatidic Acid; Physiological; Play; Protein Isoforms; Proteins; Receptor Signaling; Rest; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Structure; T cell anergy; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Transcription Factor AP-1; base; c-myc Genes; improved; insight; mutant; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance

DESCRIPTION (provided by applicant): Most T cells in healthy individuals are in a naïve resting or quiescent state. Quiescence ensures the maintenance of the vast repertoire of T cells in a defined space by preventing uncontrolled polyclonal expansion. Recent evidence indicates that T cell quiescence is actively programmed and maintained. However, the mechanisms that control T cell quiescence are poorly understood. The maintenance of steady-state naïve CD8 T cells relies on orchestrated signaling from the IL-7 receptor and the T cell antigen receptor (TCR). TCR signaling is initiated after the engagement of the TCR with major histocompatibility complex I molecules loaded with self-peptides. How such tonic TCR signaling is tightly controlled to prevent full T cell activation is poorly understood. Diacylglycerol kinases (DGKs) are enzymes that convert diacylglycerol (DAG) to phosphatidic acid (PA), both important second messengers involved in activating in multiple signaling pathways and regulate diverse cellular processes and functions. In mammals, ten DGK isoforms exist yet their physiological functions are poorly understood. We have found that deficiency of both DGKα and ζ, the major isoforms expressed in T cells, causes na�ve T cells to lose quiescence, leading to acquisition of effector function. Furthermore, DGKα and ζ double deficient mice develop severe autoimmune diseases with T cells play critical roles. The objectives of this application are to investigate mechanisms that control CD8 T cell quiescence using conditional DGKα and ζ deficient mice as a model and to perform thorough structure/function analysis of DGKζ in primary T cells using newly generated mice that conditionally express WT and mutant GFP-DGKζ fusion proteins. We will test the hypotheses that DGKα and ζ modulate multiple signaling pathways including mTOR signaling to ensure T cell tolerance and quiescence and that DGKζ directs its localizations and interactions via distinct structural domains/motifs, enabling it to function in multiple subcellular compartments as a critical regulator in T cells. We will pursue the following two specific aims. In Aim 1, we will investigate mechanisms that are controlled by DGKα and ζ to ensure CD8 T cell quiescence. In Aim 2, we will determine structural features critical for DGKζ to function as a critical regulator for T cell development and tolerance. Studies proposed in this application will provide novel insight into the signaling control of T cell development and quiescence and how DGKζ fulfills its critical regulatory roles in T cells.

描述（由申请人提供）：健康个体中的大多数T细胞处于naïve静息或静止状态。静止通过防止不受控制的多克隆扩增，确保在一个确定的空间内维持大量的T细胞。最近的证据表明，T细胞的静止是主动编程和维持的。然而，控制T细胞静止的机制尚不清楚。稳态naïve CD8 T细胞的维持依赖于IL-7受体和T细胞抗原受体（TCR）的协调信号。TCR信号是在TCR与装载自肽的主要组织相容性复合体I分子结合后启动的。这种强直性TCR信号是如何被严格控制以阻止T细胞的完全激活的，目前尚不清楚。二酰基甘油激酶（DGKs）是将二酰基甘油（DAG）转化为磷脂酸（PA）的酶，两者都是重要的第二信使，参与激活多种信号通路并调节多种细胞过程和功能。在哺乳动物中，存在十种DGK亚型，但它们的生理功能尚不清楚。我们发现，在T细胞中表达的主要同工异构体DGKα和ζ缺乏症会导致幼稚的T细胞失去静止状态，从而获得效应功能。此外，DGKα和ζ双缺陷小鼠发生严重的自身免疫性疾病，T细胞起关键作用。本应用程序的目的是研究控制CD8 T细胞静止的机制，使用条件DGKα和ζ缺陷小鼠作为模型，并使用新生成的小鼠条件表达WT和突变GFP-DGKζ融合蛋白，对原代T细胞中的DGKζ进行彻底的结构/功能分析。我们将测试DGKα和ζ调节多种信号通路（包括mTOR信号通路）以确保T细胞耐受和静止的假设，DGKζ通过不同的结构域/基元指导其定位和相互作用，使其能够在多个亚细胞区室中作为T细胞的关键调节剂发挥作用。我们将努力实现以下两个具体目标。在Aim 1中，我们将研究由DGKα和ζ控制的机制，以确保CD8 T细胞静止。在目标2中，我们将确定DGKζ作为T细胞发育和耐受性的关键调节因子的关键结构特征。在这个应用中提出的研究将为T细胞发育的信号控制提供新的见解