Regulation of monocyte trafficking into lymph nodes during inflammation

炎症期间单核细胞运输至淋巴结的调节

• 批准号: 10335158
• 负责人: Jessica Huang
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335158
• 关键词: Address; Adjuvant; Agonist; Biological Assay; Blood Circulation; Blood Vessels; Bone Marrow; CCL2 gene; Cell Adhesion Molecules; Cell Line; Cells; Chimera organism; Data; Dendritic Cells; Disease; Effector Cell; Flow Cytometry; Gene Expression; Gene Expression Profiling; Generations; Genetic; High Endothelial Venule; Home; Image; Imaging Techniques; Immune; Immune response; Immunity; Immunization; Infection; Infiltration; Inflammation; Innate Immune System; Intercellular adhesion molecule 1; Interleukin-12; Knock-out; Label; Lead; Learning; Mediating; Molecular; Molecular Profiling; Mus; Peripheral; Play; Population; Process; Property; Regulation; Research; Role; Shapes; Site; System; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Vaccination; Vaccine Design; Vascular Endothelium; Virus Diseases; West Nile viral infection; adaptive immunity; cell type; chemokine; cytokine; draining lymph node; effector T cell; experimental study; functional disability; innovation; insight; interest; intravital microscopy; lymph nodes; migration; molecular phenotype; monocyte; mouse model; multiplexed imaging; novel; novel strategies; recruit; spatiotemporal; trafficking; transcriptome sequencing; two-photon

Project Summary/Abstract Cells of the innate immune system play an integral role in the generation of adaptive immunity. Most notably, conventional dendritic cells play well-established roles in T cell activation and differentiation within lymph nodes during inflammation. In addition to dendritic cells, other innate cell types also contribute. Of specific interest are monocytes, which are a highly mobile population of cells, capable of acquiring distinct functions and fates tuned to the tissue they are recruited to and the type of inflammation encountered. Our recent studies (currently in revision) reveal that during vaccination or viral infection, monocytes rapidly infiltrate the draining lymph nodes in large numbers, where they functionally cooperate with the dendritic cells to drive full effector T cell differentiation. Thus, in settings of vaccination and infection, recruited monocytes play a profound role in shaping T cell immunity. However, the specific mechanisms that regulate monocyte infiltration of the lymph nodes remain unclear. In recent experiments we have found that monocytes primarily traffic into the lymph nodes via local blood vessels. These blood vessels are heavily lined with dendritic cells, which appear to be necessary for monocyte recruitment. Inflammation also induces marked changes in both the composition and molecular profile of these vessel-associated dendritic cells, including expression of specific chemokines and adhesion molecules. Together, these data lead to the central hypothesis of this proposal, that a specialized dendritic cell subset preferentially localizes near blood vessels during inflammation and regulates monocyte trafficking into lymph nodes to promote the generation of immune responses. The current proposal will utilize cutting-edge imaging techniques, gene expression studies, and functional assays to understand the cellular and molecular mechanisms by which dendritic cells regulate monocyte trafficking into lymph nodes during inflammation. In Specific Aim 1, we will examine the cellular and molecular profile of vasculature-associated dendritic cells during steady state and inflammation, and identify which subset regulates monocyte trafficking. In Specific Aim 2, we will investigate the molecular mechanisms utilized by these vessel-associated dendritic cells to promote monocyte entry. Given that monocytes are a highly plastic and mobilizable population of cells, capable of playing diverse roles in vaccination, infection, and disease, learning how to regulate monocyte trafficking will lead to innovative strategies for the design of vaccines and therapeutics.

项目总结/文摘