Determination of molecular basis of immunoregulation of human T cell circuit and its clinical significances

在本研究中，我们试图明确CD26和CD27分子在T细胞免疫调节中的分子基础及其临床意义。为了描述CD27介导的信号在B细胞应答中的作用，我们比较了CD27和cd40连接对B细胞增殖、IgG产生和细胞表型的影响。我们证明，与CD40相反，CD27信号在B细胞增殖中起次要作用，其主要功能在B细胞分化过程中被延迟，是促进生成igg细胞的形成。CD26是一种110 kDa的细胞表面糖蛋白，具有二肽基肽酶IV （DPPIV; EC3.4.14.5）酶活性，在T细胞共刺激中起重要作用。利用β趋化因子作为趋化剂，研究了CD26/二肽基肽酶IV在跨内皮细胞迁移中的功能。当可溶性重组CD26 （CD26/DPPIV^+）加入到跨内皮趋化系统时，T细胞向RANTES的趋化性和迁移性显著增强。将sCD26添加到50 ng/ml的RANTES中，与单独使用RANTES相比，其迁移反应增强了两倍，而缺乏DPPIV酶活性的突变型可溶性CD26对RANTES诱导的T细胞迁移没有增强作用。在分析sCD26增强T细胞迁移的机制过程中，我们发现RANTES在生理条件下被sCD26在其酶特异性特征的精确位点上切割。然而，缺乏两个n端氨基酸的合成RANTES在T细胞上表现出与全长RANTES相当的趋化活性。此外，sCD26的加入还能增强两种RANTES诱导的T细胞迁移。与T细胞相比，截断的RANTES对纯化的单核细胞的趋化性不活跃，补充sCD26而不是mCD26降低了单核细胞对RANTES的迁移反应。这些结果表明，CD26/DPPIV对T细胞和单核细胞对RANTES的趋化反应有差异调节，此外，这一发现可以部分解释CD26高阳性细胞在体外具有最大的迁移能力，并且是体内慢性炎症部位的显性表型。少

In the present study, we attempted to define the molecular basis of role of CD26 and CD27 molecules in T cell immune regulation and their clinical significances. To characterize the role of CD27-mediated signaling in B cell responses, we have compared the effects of CD27 and CD4O ligation on B cell proliferation, IgG production, and cell phenotype. We demonstrate that, in contrast to CD40, CD27 signaling plays a minor role in B proliferation and that its major function, which is delayed during the process of B cell differentiation, is to contribute to the formation of Ig-producing cells.CD26, a 110 kDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV (DPPIV ; EC3.4.14.5) enzyme activity and plays an important role in T cell costimulation. The function of CD26/dipeptidyl peptidase IV in transendothelial migration was examined using beta-chemokines as chemoattractants. When soluble recombinant CD26 (CD26/DPPIV^+) was added to the transendothelial chemotaxis system, chemotactic … More migration of T cells toward RANTES was significantly enhanced. Addition of sCD26 to 50 ng/ml of RANTES enhanced the migratory response by a factor of two compared to RANTES alone, whereas mutant soluble CD26, lacking the DPPIV enzyme activity, had no enhancing effect on RANTES-induced T cell migration. In the process of analyzing the mechanisms of the enhancement of T cell migration by sCD26, we showed that RANTES was cleaved by sCD26 under physiologic conditions at the precise site characteristic of its enzyme specificity. However, synthesized RANTES which lacks two N-terminal amino acids showed a chemotactic activity equivalent to full length RANTES on T cells. Furthermore, addition of sCD26 showed enhancement of T cell migration induced by both forms of RANTES.In contrast to T cells, the truncated RANTES is inactive in chemotaxis of purified monocytes, and supplement of sCD26 but not mCD26 reduced the migratory response of monocytes to RANTES.These results suggest that CD26/DPPIV differentially regulate the chemotactic response of T cells and monocytes to RANTES and furthermore, the finding can partly explain the observation that CD26 highly positive cells have most migratory capacity in vitro and were the dominant phenotype at the chronic inflammatory sites in vivo. Less