Analysis of mechanisms by which CD8^+ T cells differentiate into the skin-homing phenotype

CD8^T细胞分化为皮肤归巢表型的机制分析

基本信息

批准号：
15390344
负责人：
SHIOHARA Tetsuo
金额：
$ 9.6万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

In this study, we asked how expression of two fucosyltransferases (Fuc Ts), Fuc T-IV and Fuc T-VII, can be regulated in the process of skin-homing CD8^+ T cell differentiation. We demonstrated with the use of transfectants that E-selectin ligand (ESL) epitope generated by Fuc T-IV is different from that generated by Fuc T-VII ; and that Fuc T-IV generates only low. levels of ESL without CLA expression while Fuc T-VII constructs high levels of ESL with concomitant expression of CLA. Our phenotypic analysis of memory CD8^+ T cells differentiated from naive T cells under various conditions showed that the transition from the ESL^+CLA^- to the ESL^<++>CLA^+ phenotype progressively occurred in parallel with down-regulation of Fuc T-IV expression when transferred to resting culture with IL-12. In contrast, Fuc T-VII expression was down-regulated as the T cells were transferred to IL-4-rich resting culture, where Fuc T-IV remained unchanged and the ESL^<++>CLA^+ phenotype was not detected. These results indicate that under conditions where Fuc T-IV is abundantly expressed the Fuc T-VII-dependent ESL is prevented from cell surface expression ; however, once availability of the substrate, N-acetyllactosamine, is limited, Fuc T-IV is down-regulated due to competition of this substrate, thereby allowing the T cell to express the Fuc T-VII-dependent ESL epitope with high avidity to E-selectin. Thus, the dynamic balance between Fuc T-IV and Fuc T-VII depending on their state of a activation and differentiation is a major check point for the regulation of skin-homing CD8^+ T cell differentiation.

在本研究中，我们探讨了两种岩藻糖基转移酶 (Fuc Ts)、Fuc T-IV 和 Fuc T-VII 的表达如何在皮肤归巢 CD8^+ T 细胞分化过程中受到调节。我们使用转染子证明了 Fuc T-IV 产生的 E-选择素配体 (ESL) 表位与 Fuc T-VII 产生的不同。 Fuc T-IV 的生成量很低。 Fuc T-VII 构建高水平的 ESL，同时表达 CLA。我们对各种条件下从初始 T 细胞分化而来的记忆 CD8^+ T 细胞的表型分析表明，从 ESL^+CLA^- 到 ESL^<++>CLA^+ 表型的转变与下调同时发生。当转移至含有 IL-12 的静息培养物时，Fuc T-IV 表达的变化。相反，当T细胞转移至富含IL-4的静息培养物时，Fuc T-VII表达下调，其中Fuc T-IV保持不变并且未检测到ESL^++CLA^+表型。这些结果表明，在 Fuc T-IV 大量表达的条件下，Fuc T-VII 依赖性 ESL 被阻止在细胞表面表达；然而，一旦底物 N-乙酰乳糖胺的可用性受到限制，Fuc T-IV 由于该底物的竞争而下调，从而允许 T 细胞以高亲和力表达 Fuc T-VII 依赖性 ESL 表位E-选择素。因此，Fuc T-IV 和 Fuc T-VII 之间的动态平衡取决于它们的激活和分化状态，是调节皮肤归巢 CD8^+ T 细胞分化的主要检查点。