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Published online before print April 20, 2007

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(Journal of Leukocyte Biology. 2007;82:93-105.)
© 2007 by Society for Leukocyte Biology

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

Sandra Tuyaerts^*,1, Sonja Van Meirvenne^*,1, Aude Bonehill^*, Carlo Heirman^*, Jurgen Corthals^*, Herman Waldmann, Karine Breckpot^*, Kris Thielemans^* and Joeri L. Aerts^*,2

^* Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel, Brussels, Belgium; and
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

² Correspondence: Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the VUB, Laarbeeklaan 103/E, 1090 Brussels, Belgium. E-mail: joeri.aerts{at}vub.ac.be

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.

Key Words: GITR • vaccination • costimulation • immunotherapy

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