Tuyaerts Sandra, Van Meirvenne Sonja, Bonehill Aude, Heirman Carlo, Corthals Jurgen, Waldmann Herman, Breckpot Karine, Thielemans Kris, Aerts Joeri L
Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium.
J Leukoc Biol. 2007 Jul;82(1):93-105. doi: 10.1189/jlb.0906568. Epub 2007 Apr 20.
CD4(+)CD25(+) regulatory T cells (Treg) have been described as an important hurdle for immunotherapy. Engagement of glucocorticoid-induced TNF receptor-related protein (GITR) has emerged recently as an important mechanism to control the suppression of CD4(+)CD25(+) Treg. Furthermore, it has been documented extensively that GITR ligation is costimulatory for naive and activated T cells in the murine setting. However, little is known about the role of the human GITR ligand (huGITRL). We wanted to explore whether huGITRL could enhance antigen-specific T cell priming by dendritic cells (DC). First, we confirmed the endogenous expression of GITRL on HUVEC. We also detected GITRL expression on EBV-B cell lines, whereas no GITRL expression was observed on human monocyte-derived DC. Electroporation of GITRL mRNA in monocyte-derived DC resulted in a strong and long-lasting surface expression of GITRL. In contrast to data obtained in mice, no significant abrogation of Treg suppression by GITRL-expressing human DC was observed. Consistent with our mouse data, we showed that huGITRL is costimulatory for responder T cells. Furthermore, we found that GITRL-expressing DC primed increased numbers of Melan-A-specific CD8(+) T cells. We conclude that although huGITRL is not capable of alleviating Treg suppression of responder T cells, huGITRL overexpression on monocyte-derived DC enhances their capacity to induce antigen-specific T cell responses. Thus, GITRL incorporation in DC might improve the antitumor immune response after vaccination.
CD4(+)CD25(+)调节性T细胞（Treg）被认为是免疫治疗的一个重要障碍。糖皮质激素诱导的TNF受体相关蛋白（GITR）的参与最近已成为控制CD4(+)CD25(+) Treg抑制作用的重要机制。此外，已有大量文献记载，在小鼠模型中，GITR连接对幼稚和活化的T细胞具有共刺激作用。然而，关于人GITR配体（huGITRL）的作用却知之甚少。我们想探讨huGITRL是否能增强树突状细胞（DC）介导的抗原特异性T细胞启动。首先，我们证实了GITRL在人脐静脉内皮细胞（HUVEC）上的内源性表达。我们还检测到EBV-B细胞系上有GITRL表达，而在人单核细胞来源的DC上未观察到GITRL表达。将GITRL mRNA电穿孔导入单核细胞来源的DC后，可导致GITRL在细胞表面强烈且持久地表达。与在小鼠中获得的数据相反，未观察到表达GITRL的人DC对Treg抑制作用有明显的消除作用。与我们在小鼠中的数据一致，我们发现huGITRL对反应性T细胞具有共刺激作用。此外，我们发现表达GITRL的DC启动了更多数量的Melan-A特异性CD8(+) T细胞。我们得出结论，尽管huGITRL不能减轻Treg对反应性T细胞的抑制作用，但单核细胞来源的DC上过表达huGITRL可增强其诱导抗原特异性T细胞反应的能力。因此，将GITRL整合到DC中可能会改善疫苗接种后的抗肿瘤免疫反应。
