Structure Function Analysis of T Cell E-Selectin Ligands

描述(由申请人提供)：白细胞从血液中重新聚集到皮肤炎症部位，通过一连串的粘连事件发生。T细胞向皮肤炎症部位的运输与皮肤淋巴细胞抗原(CLA)的表达密切相关，CLA是一种碳水化合物表位，作为T细胞上的E-选择素配体，介导T细胞募集的第一个关键步骤。此前已有研究表明，CLA在一种名为P-选择素糖蛋白配体-1(PSGL-1)的白细胞唾液酸粘蛋白上有差异表达。我们最近发现与PSGL-1结构相似的唾液粘蛋白CD43和未知的100kD唾液酸糖蛋白(Gpl00)也可以作为CLA T细胞上的E-选择素配体。这些以前未知的T细胞选择素配体是用我们开发的两种新的检测方法鉴定出来的。目前，还没有关于CD43上的E-选择素配体决定簇或T细胞上的100kD糖蛋白的结构或调节的公开数据。这些以前未知的配体可能在免疫监测和白细胞向炎症部位的募集中发挥重要的、目前尚未确定的作用。在这一应用中，我们概述了将表征T细胞上表达的单个E-选择素配体的实验。识别这些配体之间的共同基序可以直接导致设计和开发共同的E-选择素介导的黏附抑制剂，这可能在慢性自身免疫病、移植物抗宿主病和移植排斥等炎症性疾病中具有重要价值。

DESCRIPTION (provided by applicant): Recruitment of leukocytes from blood into cutaneous inflammatory sites occurs via a stepwise cascade of adhesion events. T cell trafficking to sites of cutaneous inflammation has been closely associated with expression of the cutaneous lymphocyte antigen (CLA), a carbohydrate epitope that serves as an E-selectin ligand on T cells and mediates the first, crucial steps in T cell recruitment. CLA has been shown previously to be differentially expressed on a leukocyte sialomucin called P-selectin glycoprotein ligand-1 (PSGL-1). We have recently discovered that CD43, a sialomucin similar in structure to PSGL-1, and an unidentified 100kD sialoglycoprotein (gpl00) can also serve as E-selectin ligands on CLA+ T cells. These previously unknown T cell selectin ligands were identified using two novel assay methods we have developed. There is, at present, no published data regarding the structure or regulation of E-selectin ligand determinants on CD43 or a 100 kD glycoprotein on T cells. These previously unknown ligands may play important, currently undefined roles in immune surveillance and the recruitment of leukocytes to inflammatory loci. In this application, we outline experiments that will characterize the individual E-selectin ligands expressed on T cells. The identification of common motifs among these ligands could lead directly to the design and development of common inhibitors of E-selectin mediated adhesion that may be of significant value in inflammatory disorders such as chronic autoimmune disease, graft-versus-host disease and transplantation rejection.