Endothelial regulation of IL17 producing T effector cell migration

内皮调节产生 IL17 的 T 效应细胞迁移

• 批准号: 8515502
• 负责人: Maria Pilar Alcaide Alonso
• 金额: $ 23.7万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515502
• 关键词: Address; Adhesions; Autoimmune Diseases; Award; Behavior; Biological Assay; CCL20 gene; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cells; Cytokine Signaling; Data; Disease; E-Selectin; Effector Cell; Endothelium; Funding; Goals; Helper-Inducer T-Lymphocyte; Homing; IL17 gene; Immune System Diseases; In Vitro; Infection; Inflammation; Inflammatory; Instruction; Intercellular adhesion molecule 1; Interleukin-17; Knowledge; Ligands; Mediating; Methods; Modeling; Mus; Organ; P-Selectin; Pathologic; Pathology; Phase; Phenotype; Physiological; Process; Regulation; Research Design; Research Project Grants; Site; Surface; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Techniques; Th1 Cells; Tissues; Vascular Endothelial Cell; Work; base; cell motility; cell type; chemokine; chemokine receptor; in vivo; in vivo Model; microbial; migration; monolayer; response

Different subsets of effector T ceils contribute in distinct ways to various pathologic conditions. Their migration into tissues is a highly regulated process that involves interactions of the T cells with vascular endothelial cells. IL-17 producing T helper cells (Th17), a newly defined T cell subset that is pro-inflammatory, can contribute to the inflammatory pathology of organ specific autoimmune diseases, as well as to protective responses against certain microbial infections. The overall aim of this project is to study the regulation of migration of Th17 cells into inflammatory sites with the goal of determining if their homing into tissues can be specifically targeted in therapeutically useful ways. Based on data generated during the K99 funding period, my working hypothesis is that Th17 cells have a different migratory phenotype than Th1 cells, a T cell type that also promotes inflammation. I have established several new in vitro and in vivo assays that will be used to address my specific aims during the ROO phase of this award. In Aims 1 and 2, the major findings were that (i) Th17 show more robust surface expression of E-selectin ligands including glycoCD43 and as a result adhere more to E-selectin than P-selectin; (ii) that Th17 cells express high levels of the chemokine receptor 6 (CCR6) and readily increase their adhesion to ICAM-1 and TNF-activated endothelial monolayers in the presence ofthe CCR6 ligand, CCL20 under physiological shear flow conditions. Thus Th17 rolling and chemokine activated arrest are important steps during the recruitment to tissues and my findings open a window to explore the existence of as yet unidentified E-Selectin ligands that may be exclusively expressed on Th17 cells. This goal is now incorporated into revised Aims 1 and 2. Similar to what I have done during the K99 award, Aim 3 will interplay with Aims 1 and 2 and will explore using in vivo techniques the relevance of this as yet undefined E-selectin ligand during Th17 cell recruitment in models of inflammation.

效应T细胞的不同亚群以不同的方式促成各种病理状况。他们的 向组织中的迁移是一个高度调节的过程，涉及T细胞与 血管内皮细胞产生IL-17的T辅助细胞（Th 17），一种新定义的T细胞亚群， 是促炎性的，可以促进器官特异性自身免疫性的炎症病理学， 疾病，以及对某些微生物感染的保护性反应。的总体目标 本项目旨在研究Th 17细胞向炎症部位迁移的调节， 以确定它们归巢到组织中是否能以治疗有用的方式特异性靶向。 根据K99资助期间产生的数据，我的工作假设是Th 17细胞 具有与Th 1细胞不同的迁移表型，Th 1细胞是一种也促进炎症的T细胞类型。我 我已经建立了几个新的体外和体内试验，将用于解决我的具体 在这个奖项的ROO阶段的目标。在目标1和2中，主要发现是（i）Th 17 显示出E-选择素配体（包括glycoCD 43）的更强的表面表达， 与P-选择素相比，粘附更多E-选择素;（ii）Th 17细胞表达高水平趋化因子 受体6（CCR 6），并容易增加其粘附ICAM-1和TNF-活化的内皮细胞 在生理剪切流条件下，CCR 6配体CCL 20存在下的单层。 因此，Th 17滚动和趋化因子激活的停滞是募集过程中的重要步骤， 组织和我的发现打开了一扇窗户，探索尚未确定的E-选择素的存在。 配体，其可以仅在Th 17细胞上表达。这一目标现已纳入经修订的 目标1和2。与我在K99颁奖期间所做的类似，目标3将与目标1相互作用 和2，并将探索使用体内技术的相关性，这尚未确定的E-选择素 在炎症模型中Th 17细胞募集过程中的配体。