REGULATION OF T CELL SELECTIN LIGAND EXPRESSION

许多组织限制性自身免疫性和炎症性疾病，包括 关节炎、银屑病和皮肤T细胞淋巴瘤的特征在于： 记忆T细胞浸润。 发展和进步，这些 疾病是受记忆T细胞的能力，以回家， 以一种高度特异性的方式攻击目标。 虽然淋巴细胞 运输到次级免疫组织是很好的研究， 调节T细胞归巢至非免疫组织的机制仍然不清楚。 如同 其他白细胞，T细胞可以通过血管壁束缚和滚动。 选择素作为多步途径的起始部分， 外渗到组织中。 慢性发炎的组织 发现表达高水平的E-选择素（皮肤）或P-选择素 （关节）。 内皮选择素的白细胞配体是 表面表达的唾液酸化岩藻糖基化碳水化合物 糖蛋白 我们有初步证据表明 外周血T细胞表达其E-选择素的主要配体 和P-选择素在相同的蛋白质支架上，P-选择素糖蛋白 配体-1（PSGL-1），并可调节碳水化合物 这些配体的一部分独立地。 报告显示，PSGL-1可能 也具有L-选择素配体活性，尽管这与 其它配体未知。 本文中要检验的具体假设 提出：1）T细胞E-选择素、P-选择素和L-选择素配体 活性独立地表达在共同的PSGL-1蛋白上 支架作为结构和功能上不同的翻译后 修饰;和2）用赋予PSGL-1的表位修饰PSGL-1， 选择素配体活性通过α-1，3- 岩藻糖基转移酶，相关碳水化合物的末端组分 生物合成级联 这些假设将被直接检验， 在本提案的具体目标中概述。 识别 控制白细胞选择素配体产生的机制可以 确定干预调节T细胞归巢的途径， 慢性炎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.