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

本研究试图明确CD26和CD27分子在T细胞免疫调节中作用的分子基础及其临床意义。为了研究CD27介导的信号在B细胞反应中的作用，我们比较了CD27和CD4O结扎对B细胞增殖、免疫球蛋白G产生和细胞表型的影响。我们证明，与CD40相比，CD27信号在B细胞增殖中的作用较小，其主要功能是促进产生免疫球蛋白的细胞的形成。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)活性，在T细胞共刺激中发挥重要作用。以β-趋化因子为趋化因子，检测CD26/二肽基肽酶IV在跨内皮细胞迁移中的作用。当可溶性重组CD2 6(CD2 6/DPPIV^+)加入经内皮细胞趋化系统时，趋化…更多的T细胞向RANTES迁移明显增强。在50 ng/mlRANTES中加入sCD26，与单独加入RANTES相比，迁移反应增强2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促进T细胞迁移的机制的过程中，我们发现在生理条件下，RANTES被sCD26在其酶特异性的精确位置上切割。然而，缺少两个N端氨基酸的人工合成的RANTES对T细胞的趋化活性与全长RANTES相当。与T细胞相比，截短的RANTES对纯化的单核细胞的趋化作用不明显，补充sCD26而不补充mCD26则降低了单核细胞对RANTES的趋化反应。这些结果提示CD26/DPPIV对T细胞和单核细胞对RANTES的趋化反应具有不同的调节作用，这一发现可以部分解释CD26高表达细胞在体外具有最大的趋化能力，并且是体内慢性炎症部位的主要表型。较少

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