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.

项目总结