REGULATION OF T CELL SELECTIN LIGAND EXPRESSION

许多组织限制性自身免疫和炎症性疾病，包括 关节炎、牛皮癣和皮肤T细胞淋巴瘤的特征是 记忆T细胞的渗入。这些技术的发展和进展 障碍受记忆T细胞归巢能力的影响 他们的目标网站以高度具体的方式。虽然淋巴细胞 转运到次级免疫组织已经得到了很好的研究，其机制 调节T细胞归巢到非免疫组织的机制仍然不清楚。和以前一样 其他白细胞，T细胞可以通过以下途径在血管壁上系系和滚动 选择素作为多步骤途径的初始部分 渗入组织。慢性发炎的组织已经 发现高水平的E-选择素(皮肤)或P-选择素 (关节)。内皮细胞选择素的白细胞配体是 表面表达的唾液酸岩藻糖化碳水化合物 糖蛋白。我们有初步证据表明 外周血T细胞表达E-选择素的主要配体 和P-选择素在同一蛋白支架上，P-选择素糖蛋白 配体-1(PSGL-1)，并能调节碳水化合物的表达 这些配体的一部分是独立的。报道称，PSGL-1可能 还具有L-选择素配基活性，通过与此的关系 其他配体尚不清楚。在这方面要检验的具体假设 建议：1)T细胞E-选择素、P-选择素和L-选择素配体 活性在共同的PSGL-1蛋白上独立表达 作为翻译后结构和功能截然不同的脚手架 修饰；2)修饰PSGL-1，赋予表位 选择素配体活性受α-1，3- 岩藻糖基转移酶，相关碳水化合物的末端成分 生物合成级联反应。这些假设将被直接测试为 在这项提案的具体目标中概述。身份识别 控制白细胞选择素配体产生的机制可能 确定干预调节T细胞归巢的途径 慢性炎症性疾病和淋巴肿瘤转移。

Many tissue-restricted autoimmune and inflammatory disorders, including arthritis, psoriasis and cutaneous T cell lymphoma, are characterized by infiltrates of memory T cells. Development and progression of these disorders is influenced by the ability of memory T cells to home to their target sites in a highly specific fashion. Although lymphocyte trafficking to secondary immune tissues is well-studied, the mechanisms regulating T cell homing to non-immune tissues remain obscure. As with other leukocytes, T cells can tether and roll on vessel walls via selectins as the initial part of a multi-step pathway leading to extravasation into tissues. Chronically inflamed tissues have been found to express high levels of E-selectin (cutaneous) or P-selectin (joints). Leukocyte ligands for the endothelial selectins are sialylated, fucosylated carbohydrates expressed on surface glycoproteins. We have preliminary evidence that subpopulations of peripheral blood T cells express their primary ligands for E-selectin and P-selectin on the same protein scaffold, P-selectin glycoprotein ligand-1 (PSGL-1), and can regulate expression of the carbohydrate portion of these ligands independently. Reports suggest that PSGL-1 may also bear L-selectin ligand activity, though the relationship of this to other ligands is unknown. The specific hypotheses to be tested in this proposal are: 1) T cell E-selectin, P-selectin and L-selectin ligand activities are independently expressed on a common PSGL-1 protein scaffold as structurally and functionally distinct post-translational modifications; and 2) decoration of PSGL-1 with epitopes conferring selectin ligand activity is regulated via the activity of alpha-1,3- fucosyltransferases, the terminal component of the relevant carbohydrate biosynthesis cascade. These hypotheses will be directly tested as outlined in the specific aims of this proposal. Identification of the mechanisms controlling the production of leukocyte selectin ligands may define avenues for intervention in the regulation of T cell homing in chronic inflammatory disorders and lymphoid tumor metastasis.