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

项目总结 获得性免疫监测依赖于T细胞通过次级免疫系统成功迁移的能力 淋巴组织，并与抗原提呈细胞形成免疫突触。精准组织、动态组织 肌动蛋白细胞骨架在这两个过程中都是必不可少的。在迁移的T细胞中快速重组 肌动蛋白细胞骨架对细胞极化和趋化反应是必不可少的，这是组织进入和 正确的微环境定位。在T细胞激活期间，肌动蛋白细胞骨架的变化控制着适当的 免疫突触的形成，这是一种高度组织化的细胞结构，使T细胞能够 整合来自T细胞受体的信号与来自CD28和整合素等共刺激分子的信号 如LFA-1(αLβ2)。Flitless-1(FliI)最初在果蝇中被鉴定为一种肌动蛋白修饰蛋白， 控制控制飞行的肌肉中的肌动蛋白肌原纤维结构。FliI含有一个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，并参与控制RAS的激活 ERK/MAPK信号、rac1激活和PI3K信号。FliI C末端编码6个明胶蛋白相关结构域 它可以与肌动蛋白相互作用，调节肌动蛋白细丝的组装和拆卸。基于其独特的领域 结构，我们假设FliI是CD8+T细胞动态平衡和功能的关键调节者，通过连接 细胞迁移和激活过程中肌动蛋白细胞骨架的变化与各种信号的空间调控 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 相关和创新的鼠标模型。这些研究的完成将为 调节CD8+T细胞介导的免疫的新的和完全未知的信号中枢。

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.