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

项目摘要 适应性免疫监视依赖于T细胞成功迁移通过次级免疫系统的能力。 淋巴组织，并与抗原呈递细胞形成免疫突触。精确和动态的组织 肌动蛋白细胞骨架的变化对这两个过程都是必不可少的。在迁移性T细胞中， 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是必需的， 正确的微环境定位。在T细胞活化过程中，肌动蛋白细胞骨架的变化控制着T细胞的正常功能。 免疫突触的形成，一种高度组织化的细胞结构，允许T细胞正确地 将来自T细胞受体的信号与来自共刺激分子如CD 28和整联蛋白的信号整合 如LFA-1（αLβ2）。Flightless-1（Flii）最初在果蝇中被鉴定为肌动蛋白修饰蛋白， 在控制飞行的肌肉中控制肌动蛋白肌原纤维结构。Flii含有N-末端富含亮氨酸的重复序列 (LRR)结构域，促进蛋白质-蛋白质相互作用，并已涉及控制Ras激活的 Erk/Mapk信号传导、Rac 1激活和PI 3 K信号传导。Flii C-末端编码6个凝溶胶蛋白相关结构域 可以与肌动蛋白相互作用并调节肌动蛋白丝的组装/拆卸。基于其独特的域 结构，我们假设Flii作为CD 8 + T细胞稳态和功能的关键调节因子，通过连接 肌动蛋白细胞骨架在细胞迁移和激活过程中的变化与各种信号的空间控制 瀑布我们将使用最先进的细胞和分子技术来研究Flii在生理上的功能。 相关和创新的小鼠模型。这些研究的完成将提供重要的新的见解， 新的和完全未表征的信号中枢，调节CD 8 + T细胞介导的免疫。

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.