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.

Tuyaerts S, Van Meirvenne S, Bonehill A, Heirman C, Corthals J, Waldmann H, Breckpot K, Thielemans K, Aerts JL.
J Leukoc Biol. 2007 Jul;82(1):93-105. 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.

URL: http://www.jleukbio.org/cgi/content/full/82/1/93

Pub Med: http://www.ncbi.nlm.nih.gov/pubmed/17449724

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