GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells |
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| Authors: | Igarashi Hanna Cao Yujia Iwai Hideyuki Piao Jinhua Kamimura Yosuke Hashiguchi Masaaki Amagasa Teruo Azuma Miyuki |
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| Affiliation: | a Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan
b Department of Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan |
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| Abstract: | Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25−CD4+ effector (Teff) and CD25+CD4+ regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4+ T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4+ T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists. |
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| Keywords: | Costimulation GITR ligand CD4+ T cells Regulatory T cells Effector T cells |
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