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.

在这项研究中，我们询问了如何在呈皮肤的CD8^+ T细胞分化过程中调节两个岩藻糖基转移酶（FUC TS），FUC T-IV和FUC T-VII的表达。我们证明了使用转染剂表明，FUC T-IV产生的E-选择蛋白配体（ESL）表位与FUC T-VII产生的表位不同。而FUC t-iv仅产生低。没有CLA表达的ESL的水平，而FUC T-VII构建了高水平的ESL，其伴随CLA表达。我们对在各种条件下与幼稚T细胞区分的记忆CD8^+T细胞的表型分析表明，从ESL^+Cla^ - 到ESL^<++> cla^+表型的过渡逐渐逐渐发生在与fuc t-iv表达的下调时，当fuc t-iv表达转移到静息培养物中时，fuc t-iv表达表达。相比之下，由于T细胞转移到IL-4富含的静息培养物中，FUC T-VII表达被下调，在那里FUC T-IV保持不变，并且未检测到ESL^<++> cla^+表型。这些结果表明，在大量表达FUC T-IV的条件下，FUC t-VII依赖性ESL被阻止细胞表面表达。然而，一旦底物的可用性N-乙酰甲胺胺受到限制，FUC T-IV由于该底物的竞争而被下调，从而使T细胞表达T-VII依赖性ESL依赖性ESL表位，并且对E-SELECTIN高自然。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，是调节皮肤呈CD8^+ T细胞分化的主要检查点。