HS1 Function in Dendritic Cells

树突状细胞中的 HS1 功能

• 批准号: 8142744
• 负责人: YAIR ARGON
• 金额: $ 24.87万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142744
• 关键词: Actins; Address; Adhesions; Adhesives; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; Binding; Biochemical; C-terminal; Cell membrane; Cell physiology; Cells; Cellular Structures; Co-Immunoprecipitations; Cytoskeleton; Data; Defect; Dendritic Cells; Deposition; Development; Dynamin 2; Endocytic Vesicle; Endocytosis; Exhibits; Extracellular Matrix; Future; Genetic Polymorphism; Hematopoietic; Immigration; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunotherapy; In Vitro; Inflammatory; Integrins; Intracellular Transport; Knowledge; Lead; Leukocytes; Lupus; Lymphoid; Lymphoid Tissue; Matrix Metalloproteinases; Mediating; Microscopy; Modeling; Mutation; Organ; Peptides; Peripheral; Phosphorylation; Play; Process; Proteins; Regulation; Regulatory Pathway; Role; SH3 Domains; Signal Transduction; Site; Structure; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Transport Process; Vaccines; Vesicle; Video Microscopy; Work; base; cell motility; genetic regulatory protein; in vivo; insight; leukemia; lymph nodes; migration; mutant; neoplastic cell; pathogen; polymerization; public health relevance; receptor; receptor mediated endocytosis; research study; response; uptake

DESCRIPTION (provided by applicant): Dendritic cells (DCs) play a pivotal role in the immune response, by collecting pathogens and tumor cell debris in peripheral tissues, and delivering these as peptides to lymph nodes for presentation to T cells. DC function relies heavily on the actin cytoskeleton, and mutations in actin-regulatory proteins like WASp lead to defects in DC function associated with immunodeficiency and autoimmunity. In T cells, we showed previously that WASp works together with another actin regulatory protein, HS1. HS1 is also expressed in dendritic cells, and our preliminary data show that HS1 is required for efficient antigen presentation. In addition, we find that HS1 is required for organization of podosomes, structures required for adhesion to the extracellular matrix and matrix metalloproteinase deposition during cell migration through tissues. We hypothesize that HS1 works together with WASp and dynamin II in DCs, to control receptor-mediated endocytosis and podosome- dependent migration to lymphoid organs. To test this hypothesis, we will carry out three Aims. First, we will test the role of HS1 interactions with dynamin II in driving vesicle internalization during receptor-mediated endocytosis, and ask if HS1 is also required for additional steps the intracellular transport and processing of internalized antigens. Second, we will investigate lamellipodial and podosome dynamics in migrating BMDCs using video microscopy, ask if HS1 is required for secretion of matrix metalloproteinases, and test the ability of HS1-/- DCs to migrate to lymph nodes in vivo. Third, we will conduct structure-function studies to test the hypothesis that the C-terminal SH3 domain of HS1 directs its actin-regulatory functions during endocytosis and migration via regulated interactions with WASp and dynamin II. Taken together, these studies will represent the first careful analysis of HS1 function in dendritic cells, and will provide important new insights into how actin regulatory pathways control specific aspects of DC function. This information will be valuable for developing therapeutic strategies for immunodeficiency and autoimmune diseases that arise as a result of mutations in actin-regulatory proteins, and for the development of effective DC-based vaccines and immunotherapies. PUBLIC HEALTH RELEVANCE: Several aspects of dendritic cell function depend on highly orchestrated changes in cell structure, and mutations in key cytoskeletal regulatory proteins lead to severe immunodeficiency or Lupus. This proposal addresses the role of one important cytoskeletal regulatory protein, HS1, in specific aspects of dendritic cell function. The knowledge gained from these studies will be important for understanding the basis of immunodeficiency and autoimmune disease, and for the development of effective dendritic cell-based vaccines.

描述（由申请人提供）：树突状细胞（DC）在免疫反应中发挥着关键作用，通过收集外周组织中的病原体和肿瘤细胞碎片，并将这些作为肽递送至淋巴结以呈递给T细胞。 DC 功能在很大程度上依赖于肌动蛋白细胞骨架，WASp 等肌动蛋白调节蛋白的突变会导致与免疫缺陷和自身免疫相关的 DC 功能缺陷。在 T 细胞中，我们之前表明 WASp 与另一种肌动蛋白调节蛋白 HS1 一起发挥作用。 HS1也在树突状细胞中表达，我们的初步数据表明HS1是有效抗原呈递所必需的。此外，我们发现 HS1 是足小体组织所必需的，足小体是细胞在组织迁移过程中粘附到细胞外基质和基质金属蛋白酶沉积所需的结构。我们假设 HS1 与 DC 中的 WASp 和动力 II 一起作用，控制受体介导的内吞作用和足小体依赖性向淋巴器官的迁移。为了检验这个假设，我们将实现三个目标。首先，我们将测试 HS1 与动力 II 相互作用在受体介导的内吞作用过程中驱动囊泡内化的作用，并询问 HS1 是否也需要用于细胞内运输和内化抗原加工的其他步骤。其次，我们将使用视频显微镜研究迁移 BMDC 时的板状足和足体动力学，询问基质金属蛋白酶的分泌是否需要 HS1，并测试 HS1-/- DC 体内迁移至淋巴结的能力。第三，我们将进行结构功能研究，以检验以下假设：HS1 的 C 端 SH3 结构域通过与 WASp 和动力 II 的调节相互作用，在内吞作用和迁移过程中指导其肌动蛋白调节功能。总而言之，这些研究将首次对树突状细胞中的 HS1 功能进行仔细分析，并将为肌动蛋白调控途径如何控制 DC 功能的特定方面提供重要的新见解。这些信息对于开发因肌动蛋白调节蛋白突变而引起的免疫缺陷和自身免疫性疾病的治疗策略以及开发有效的基于 DC 的疫苗和免疫疗法非常有价值。 公共健康相关性：树突状细胞功能的多个方面取决于细胞结构的高度协调变化，关键细胞骨架调节蛋白的突变会导致严重的免疫缺陷或狼疮。该提案阐述了一种重要的细胞骨架调节蛋白 HS1 在树突状细胞功能的特定方面的作用。从这些研究中获得的知识对于了解免疫缺陷和自身免疫性疾病的基础以及开发有效的基于树突状细胞的疫苗非常重要。

项目成果

The actin regulatory protein HS1 is required for antigen uptake and presentation by dendritic cells.

• DOI: 10.4049/jimmunol.1100870
• 发表时间: 2011-12-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Huang Y;Biswas C;Klos Dehring DA;Sriram U;Williamson EK;Li S;Clarke F;Gallucci S;Argon Y;Burkhardt JK
• 通讯作者: Burkhardt JK