CTLA-4 functions in tolerance and autoimmunity

CTLA-4 在耐受性和自身免疫中发挥作用

• 批准号: 7924628
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 31.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7924628
• 关键词: Acute; Address; Affect; Antigen-Presenting Cells; Antigens; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Binding; Biochemical; Biology; Bone Marrow; Bone Marrow Transplantation; CD28 gene; CTLA4 gene; Cell physiology; Chimera organism; Complex; Development; Diabetes Mellitus; Disease; Etiology; Genetic Polymorphism; Graves' Disease; Homeostasis; Immune; Immune Tolerance; Immune response; Immunity; Immunologics; In Vitro; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Learning; Length; Ligand Binding; Ligands; Link; Lymphoproliferative Disorders; Maintenance; Mediating; Membrane; Membrane Microdomains; Modeling; Mus; Newborn Infant; Pathway interactions; Peripheral; Play; Protein Isoforms; Proteins; Public Health; Reagent; Regulation; Role; Signal Transduction; Staging; Stimulus; Syndrome; System; T-Cell Activation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tetracyclines; Therapeutic; Transfection; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; base; insight; novel; novel therapeutic intervention; prevent; programs; receptor; response; synaptogenesis; tool; transmission process

CTLA-4 was first described as a negative regulatory molecule by our group in 1994. During the past 11 years the molecule has been extensively studied. The molecule has been shown to have an intrinsic effect on T cell activation by directly delivering negative signals to T cells to shut down activation and differentiation. In addition, there have been a number of studies suggesting an extrinsic role for CTLA-4 as the molecule has been proposed to be the effector molecule by which regulatory T cells suppress immunity. All of these "functions" have been complicated by the recent discovery that CTLA-4 can be expressed as a B7 ligand non-binding variant that controls T cell activation. In addition, polymorphisms in the CTLA-4 gene has been linked to Graves Disease and Type 1 Diabetes. Thus, in this renewal, we will continue to addreess the fundamental biology of CTLA-4. We propose to directly address both the intrinsic and extrinsic role of CTLA-4 in the regulation of initial T cell activation, ongoing autoimmune responses and maintenance of tolerance. The following specific aims are proposed: 1. To study the biochemical basis of B7 ligand-dependent and ligand-independent CTLA-4-mediated inhibition of T cell function; 2. To study the intrinsic role of CTLA-4 in T cell development, regulation of tolerance induction and development of diabetes in NOD mice; and 3. To study the intrinsic role of CTLA-4 in T cell development, regulation of tolerance induction and development of diabetes in NOD mice. We will use a combination of novel mice and reagents, combined with TCR transgenic and bone marrow chimera models to identify the cellular and mechanistic basis for CTLA-4 regulation. The results of these studies will provide insights into the mechanisms of CTLA-4 regulation of immunity, and test the the role of CTLA-4 in lymphoproliferative/homeostasis versus immune activation and tolerance are mediated by distinct extrinsic versus intrinsic pathways. Importantly, the information learned from this study may have important implications for public health for several reasons. T cells play a central role in immunity and autoimmunity. As such, any means to modulate T cell activity may lead to novel therapeutic approaches to treat these disease. Moreover, the fundamental importance of CTLA-4 in the induction and maintenance of peripheral tolerance is central to our understanding of disease etiology and current therapeutic approaches.

CTLA-4于1994年首次被我们课题组描述为负调控分子。在过去的11年里 多年来，该分子已被广泛研究。该分子已被证明具有内在作用 通过直接向 T 细胞传递负信号以关闭激活来影响 T 细胞激活 差异化。此外，许多研究表明 CTLA-4 的外在作用是 该分子被认为是调节性 T 细胞抑制免疫的效应分子。 最近发现 CTLA-4 可以表示为 控制 T 细胞激活的 B7 配体非结合变体。此外，CTLA-4基因的多态性 与格雷夫斯病和 1 型糖尿病有关。因此，在本次更新中，我们将继续解决 CTLA-4 的基础生物学。我们建议直接解决内在和外在的角色 CTLA-4 调节初始 T 细胞激活、持续的自身免疫反应和维持 宽容。提出以下具体目标： 1. 研究B7配体依赖性的生化基础 以及不依赖配体的 CTLA-4 介导的 T 细胞功能抑制； 2.研究内在 CTLA-4 在 T 细胞发育、耐受诱导调节和 NOD 糖尿病发展中的作用 老鼠； 3. 研究 CTLA-4 在 T 细胞发育、耐受诱导和调节的内在作用 NOD 小鼠糖尿病的发生。我们将使用新型小鼠和试剂的组合， 使用TCR转基因和骨髓嵌合体模型来确定细胞和机制基础 CTLA-4 调节。这些研究结果将为 CTLA-4 的机制提供见解 免疫调节，并测试 CTLA-4 在淋巴增殖/稳态与免疫中的作用 激活和耐受是由不同的外在途径和内在途径介导的。 重要的是，从这项研究中获得的信息可能对公共卫生产生重要影响 有几个原因。 T 细胞在免疫和自身免疫中发挥着核心作用。因此，任何调节手段 T 细胞活性可能会带来治疗这些疾病的新方法。此外，基本 CTLA-4 在诱导和维持外周耐受中的重要性是我们的核心 了解疾病病因和当前的治疗方法。