Control of CD8+ T cell migration and activation by Flightless-1

Flightless-1 控制 CD8 T 细胞迁移和激活

• 批准号: 10366045
• 负责人: Daniel J Campbell
• 金额: $ 21.76万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366045
• 关键词: Actins; Address; Antigen-Presenting Cells; Bundling; CCL21 gene; CD28 gene; CD8-Positive T-Lymphocytes; CDC42 gene; Cells; Cellular Immunity; Cellular Structures; Complex; Cytoplasmic Granules; Cytoskeleton; Data; Development; Distal; Drosophila genus; Embryo; Equilibrium; Exocytosis; F-Actin; Family; Family member; G Actin; Gelsolin; Genes; Growth; Homeostasis; Immunologic Surveillance; Impairment; Integrins; Knockout Mice; Leucine-Rich Repeat; Link; Lymphoid Tissue; Mature T-Lymphocyte; Mediating; Microfilaments; Molecular; Monomeric GTP-Binding Proteins; Mus; Muscle; Myofibrils; N-terminal; Peripheral; Physiological; Polymers; Positioning Attribute; Process; Protein Family; Proteins; Role; Signal Pathway; Signal Transduction; Site; Structure; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Tissues; WASP protein; actin capping protein; base; cell motility; chemokine; conditional knockout; cytotoxic; immunological synapse; immunological synapse formation; in vivo; innovation; insight; member; migration; mouse model; novel; polarized cell; protein protein interaction; response; rho

PROJECT SUMMARY Adaptive immune surveillance depends on the ability of T cells to successfully migrate through secondary lymphoid tissues and form immune-synapses with antigen-presenting cells. Precise and dynamic organization of the actin cytoskeleton is essential for both of these processes. In migrating T cells rapid reorganization of the actin cytoskeleton is essential for cell polarization and chemotactic responses required for tissue entry and proper micro-environmental positioning. During T cell activation, changes in the actin cytoskeleton control proper formation of the immunological synapse, a highly organized cellular structure that allows T cells to properly integrate signals from the T cell receptor with those from co-stimulatory molecules such as CD28 and integrins such as LFA-1 (αLβ2). Flightless-1 (Flii) was initially identified in Drosophila as an actin modifying protein that controls actin myofibril structure in the muscles that control flight. Flii contains an N-terminal leucine-rich repeat (LRR) domain that facilitates protein-protein interaction and has been implicated in control of Ras activation of Erk/Mapk signaling, Rac1 activation and PI3K signaling. The Flii C-terminus encodes 6 gelsolin-related domains that can interact with actin and regulate actin filament assembly/disassembly. Based on its unique domain structure, we hypothesize that Flii acts as a key regulator of CD8+ T cell homeostasis and function by linking changes in the actin cytoskeleton during cell migration and activation with spatial control of various signaling cascades. We will use state-of-the-art cellular and molecular techniques to study Flii function in physiologically relevant and innovative mouse models. Completion of these studies will provide important new insights into a novel and completely uncharacterized signaling hub that regulates CD8+ T cell-mediated immunity.

项目摘要 自适应免疫外表面取决于T细胞成功迁移的能力 淋巴组织并与抗原呈递细胞形成免疫同名。精确而充满活力的组织 肌动蛋白细胞骨架的两个过程至关重要。在迁移T细胞的快速重组 肌动蛋白细胞骨架对于细胞极化和组织进入所需的趋化反应至关重要 适当的微环境定位。在T细胞激活期间，肌动蛋白细胞骨架控制的变化适当 免疫突触的形成，一种高度组织的细胞结构，使T细胞正确 来自T细胞接收器的集成信号与共刺激分子（例如CD28和整联蛋白）的信号 例如LFA-1（αLβ2）。最初在果蝇中鉴定为肌动蛋白修饰蛋白 控制控制飞行的肌肉中的肌动蛋白肌原纤维结构。 FLII包含富含N端亮氨酸的重复 （LRR）促进蛋白质 - 蛋白质相互作用的结构域，并已暗示控制RAS激活 ERK/MAPK信号，Rac1激活和PI3K信号传导。 FLII C末端编码6个与凝胶素相关的域 可以与肌动蛋白相互作用并调节肌动蛋白丝组装/拆卸。基于其独特的领域 结构，我们假设FLII充当CD8+ T细胞体内稳态的关键调节剂，并通过链接起作用 细胞迁移过程中肌动蛋白细胞骨架的变化和激活各种信号的空间控制 级联。我们将使用最先进的细胞和分子技术来研究FLII在物理上的功能 相关和创新的鼠标模型。这些研究的完成将为一个重要的新见解 调节CD8+ T细胞介导的免疫史的新型和完全未表征的信号集线器。