Endothelial regulation of IL17 producing T effector cell migration

不同亚群的效应器T细胞在不同的病理条件下有不同的作用方式。他们的 迁移到组织中是一个高度受调控的过程，涉及T细胞与 血管内皮细胞。产生IL-17的T辅助细胞(Th17)，一种新定义的T细胞亚群 是促炎的，可促成器官特异性自身免疫的炎性病理 疾病，以及对某些微生物感染的保护性反应。的总体目标 该项目旨在研究Th17细胞迁移到炎症部位的调节，目的是 确定它们在组织中的归宿是否可以以治疗有用的方式进行特定的靶向。 根据K99资助期产生的数据，我的工作假设是Th17细胞 具有与Th1细胞不同的迁移表型，Th1细胞是一种同样促进炎症的T细胞类型。我 我已经建立了几种新的体外和体内测试，将用于解决我的特定 在这个奖项的Roo阶段的目标。在目标1和目标2中，主要结果是：(1)Th17 显示包括糖CD43在内的E-选择素配体的更强劲的表面表达，并因此 黏附E-选择素多于P-选择素；(Ii)Th17细胞高水平表达趋化因子 受体6(CCR6)，并容易增加其与ICAM-1和肿瘤坏死因子激活的内皮细胞的黏附 在生理剪切流条件下，存在CCR6配体、CCL20的单分子膜。 因此，Th17滚动和趋化因子激活的停滞是招募 组织和我的发现为探索尚不确定的E-选择素的存在打开了一扇窗 可能在Th17细胞上特异表达的配体。该目标现已纳入修订后的 目标1和目标2。类似于我在K99颁奖期间所做的，目标3将与目标1相互作用 和2，并将利用体内技术探索这一尚未定义的E-选择素的相关性 炎症模型中Th17细胞募集过程中的配体。

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.