Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory T cells

CD4CD25 regulatory T cells (Treg) have been described as an important hurdle for immunotherapy. Engagement of glucocorticoid-in- duced TNF receptor-related protein (GITR) has emerged recently as an important mechanism to control the suppression of CD4CD25 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 con- firmed 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-de- rived DC resulted in a strong and long-lasting sur- face expression of GITRL. In contrast to data ob- tained 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 re- sponder 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 re- sponses. Thus, GITRL incorporation in DC might improve the antitumor immune response after vaccination. J. Leukoc. Biol. 82: 93-105; 2007.