Crosstalk and the cytoskeleton in dendritic cell antigen presentation

树突状细胞抗原呈递中的串扰和细胞骨架

• 批准号: 8795050
• 负责人: Michael W Lipscomb
• 金额: $ 13.92万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795050
• 关键词: Actins; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmunity; Behavioral; Biological Assay; Biomimetics; Bundling; Cells; Clinical; Communicable Diseases; Communication; Cytoskeleton; Dendritic Cells; Development; Dominant-Negative Mutation; Engineering; Event; Gene Expression; Goals; Graft Rejection; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; Knowledge; Ligands; Ligation; Light; Link; Longitudinal Studies; Malignant Neoplasms; Measures; Membrane; Membrane Fluidity; Microtubules; Modeling; Motor; Movement; Mus; Myosin ATPase; Phosphorylation; Play; Proteins; Regulation; Research; Role; Side; Signal Transduction; Signaling Molecule; Site; T cell response; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; TRAF Domain; Tensile Strength; Therapeutic Agents; Vaccines; Work; adaptive immunity; base; combat; design; fascin; immunological synapse; insight; mutant; novel; public health relevance; receptor

 DESCRIPTION (provided by applicant): Here we seek to understand how the dendritic cell (DC) actin cytoskeleton governs antigen presentation to cognate T cells and also how bidirectional communication between the two cells can rearrange cytoskeletal networks to orchestrate immune responses. DC initiates antigen presentation by imparting context specific information to responder T cells. Correct information drives T cells to dynamically reorient their actin network towards the site of DC-T cell contact and assemble actin-linked intracellular signaling components. This results in long-term sustained signaling events that induce cell behavioral and gene expression changes, thereby leading to onset of adaptive immunity. Although contribution of the actin network in T cells is well established, little is understood of C cytoskeletal roles in antigen presentation and immunity. It is also unclear how crosstalk between DC and T cells through receptor-ligand engagement at the immunological synapse (IS) could rearrange the DC cytoskeleton to influence the myriad of T cell responses. Previous studies strongly support the DC actin network playing significant roles in antigen presentation. Additionally, our preliminary work highlights the role of CD40 signaling in rearranging the actin cytoskeletal network in DC to promote efficient antigen presentation. We hypothesize that the ability to relay communication to cognate responder T cells occurs through modulation of the DC actin cytoskeleton into stiff and rigid networks. This transition of the DC network would then support in trans mobility, assembly, and activation of responder T cell signaling molecules. In this project, we will delineate the role of CD40 signaling in directing DC to upregulate and recrui the actin-bundling protein fascin to the DC IS. In Aim 1A we will define the role of CD40 ligation in modulating differential fascin expression, phosphorylation-activation states, and localization o fascin at the IS. Aim 1B will delineate the downstream intracellular signaling events of CD40 vs. the role of CD40-CD40L clustering at the IS in regulation of fascin activities. Finally, in Aim 1C we evaluate wild type vs. dominant negative mutant fascin ability to rescue CD40-defecient DC priming of responder T cells. Results will provide a better understanding of the role the DC cytoskeleton plays in antigen presentation and propose a model for a larger framework of studies describing: (a) polarized cargo transport along actin-bundled networks; (b) receptor- ligand mobility and membrane fluidity at actin-bundled sites; and (c) microtubule network dynamics in DC and respective contribution to T cell responses. Information uncovered in these studies may provide blueprints for development of tunable artificial antigen presenting material and rational design of DC-based immunotherapies.

 描述（由申请人提供）：在这里，我们试图了解树突状细胞（DC）肌动蛋白细胞骨架如何控制同源 T 细胞的抗原呈递，以及两个细胞之间的双向通信如何重新排列细胞骨架网络以协调 DC 启动抗原呈递。通过向应答 T 细胞传递上下文特定信息，正确的信息驱动 T 细胞动态地将其肌动蛋白网络重新定向到 DC-T 细胞接触和组装的位置。肌动蛋白连接的细胞内信号传导成分会导致长期持续的信号传导事件，从而诱导细胞行为和基因表达变化，从而导致适应性免疫的发生。 C 细胞骨架在抗原呈递和免疫中的作用目前还不清楚 DC 和 T 细胞之间通过免疫突触 (IS) 上的受体-配体相互作用如何重新排列 DC 细胞骨架以影响大量 T 细胞反应。直流电此外，我们的初步工作强调了 CD40 信号传导在 DC 中重排肌动蛋白细胞骨架网络以促进有效抗原呈递的作用，我们发现，通过调节来传递与同源应答 T 细胞的通信的能力。 DC 肌动蛋白细胞骨架转变为僵硬的网络，然后 DC 网络的这种转变将支持应答 T 细胞信号分子的反式移动、组装和激活。在目标 1A 中，我们将定义 CD40 连接在调节肌成束蛋白差异表达、磷酸化激活状态和肌成束蛋白在 IS 上的定位中的作用。将描述 CD40 的下游细胞内信号转导事件与 IS 处 CD40-CD40L 簇在调节中的作用最后，在 Aim 1C 中，我们评估了野生型与显性失活突变型肌成束蛋白拯救 CD40 缺陷型 DC 启动应答 T 细胞的能力，结果将有助于更好地了解 DC 细胞骨架在抗原呈递中所起的作用，并提出了一种方法。更大的研究框架模型，描述：（a）沿着肌动蛋白捆绑网络的极化货物运输；（b）肌动蛋白捆绑位点的受体配体流动性和膜流动性； DC 中的微管网络动力学及其对 T 细胞反应的各自贡献这些研究中发现的信息可能为可调节人工抗原呈递材料的开发和基于 DC 的免疫疗法的合理设计提供蓝图。