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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

基本信息

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
项目类别：
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

项目摘要

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.