title: 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.
abstract: 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.
authors: Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium.
authors: Sandra
authors: S
authors: Tuyaerts
authors: Sonja
authors: S
authors: Van Meirvenne
authors: Aude
authors: A
authors: Bonehill
authors: Carlo
authors: C
authors: Heirman
authors: Jurgen
authors: J
authors: Corthals
authors: Herman
authors: H
authors: Waldmann
authors: Karine
authors: K
authors: Breckpot
authors: Kris
authors: K
authors: Thielemans
authors: Joeri L
authors: JL
authors: Aerts
mesh_terms: D017951:Antigen Presentation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D018274:Electroporation; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007109:Immunity; D022423:Myeloid Cells; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology*; D014470:Umbilical Cord / Q000166:cytology
chemical_list: C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors