Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cells in vitro
Endothelial inducible costimulator ligand expression is increased during human cardiac allograft rejection and regulates endothelial cell-dependent allo-activation of CD8+ T cells in vitro
复制标题
DOI：
10.1002/eji.200425727
复制
发表时间：
2005-06-01
影响因子：
5.4
通讯作者：
Dengler, TJ
中科院分区：
文献类型：
--
作者：
Klingenberg, R;Autschbach, F;Dengler, TJ
CD80/CD86以外的共刺激分子在内皮细胞(EC)依赖的CD8(+)T细胞活化中的作用尚不清楚，包括内皮特异性CTL(EC-CTL)亚群的产生。诱导共刺激分子(ICOS)及其配体(ICOSL)是CD28家族的新成员，在动物模型中介导效应T细胞的分化和移植物排斥反应。本研究分析了内皮细胞ICOSL的表达/调节及其对CD8(+)T细胞同种异体激活的影响。ICOSL在人内皮细胞上呈结构性表达。IL-1a和TNF-α以核因子-kappaB依赖的方式诱导人脐静脉内皮细胞(HUVEC)表达ICOSL。静息CD8(+)T细胞上未检测到ICOS受体，但与人脐静脉内皮细胞共培养可诱导ICOS受体表达。ICOSL阻断可使人脐静脉内皮细胞CD8(+)T细胞增殖减少70%，同时显著降低IL-2和干扰素-γ的产生。在共培养体系中加入IL-2可以克服ICOSL阻断的影响；同样，在含有IL-2的系统中，ICOSL阻断不影响EC-CTL的产生。在体内，ICOSL在冠状动脉微血管上有微弱的结构性表达，在急性心脏移植排斥反应中显著上调(p=0.04)。我们的数据表明ICOSL在EC介导的CD8(+)T细胞共刺激中具有明显的作用，这与人类心脏移植排斥反应有关。
The role of costimulatory molecules other than CD80/CD86 in endothelial cell (EC)-dependent CD8(+) T cell activation including the generation of a distinct subset of endothelium-specific CTL (EC-CTL) remains unclear. Inducible costimulator (ICOS) and its ligand (ICOSL) are new members of the CD28 family mediating effector T cell differentiation and graft rejection in animal models. In this study endothelial ICOSL expression/regulation and effects on CD8(+) T cell allo-activation were analyzed. Constitutive expression of ICOSL was found on human EC. IL-1a and TNF-alpha induced ICOSL in an NF-kappa B-dependent manner on human umbilical vein endothelial cells (HUVEC). ICOS receptor was not detected on resting CD8(+) T cells but was induced in co-cultures with HUVEC. ICOSL blockade reduced CD8(+) T cell proliferation by 70% along with a marked decrease of IL-2 and IFN-gamma production in co-cultures with HUVEC. IL-2 supplementation of co-cultures could overcome the effect of ICOSL blockade; similarly the generation of EC-CTL was not impaired by ICOSL blockade in an IL-2-containing system. In vivo, weak constitutive ICOSL expression was found on coronary microvessels, which was significantly up-regulated during acute cardiac allograft rejection (p=0.04). Our data indicate a distinct role for ICOSL in EC-mediated CD8(+) T cell costimulation with implications for human cardiac allograft rejection.