Article abstract
Nature Medicine 13, 579 - 586 (2007)
Published online: 8 April 2007 | doi:10.1038/nm1563
Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy
Ursula Grohmann1, Claudia Volpi1, Francesca Fallarino1, Silvia Bozza1, Roberta Bianchi1, Carmine Vacca1, Ciriana Orabona1, Maria L Belladonna1, Emira Ayroldi2, Giuseppe Nocentini2, Louis Boon3, Francesco Bistoni1, Maria C Fioretti1, Luigina Romani1,4, Carlo Riccardi2,4 & Paolo Puccetti1,4
Abstract
Glucocorticoid-induced tumor necrosis factor receptor (GITR) on T cells and its natural ligand, GITRL, on accessory cells contribute to the control of immune homeostasis. Here we show that reverse signaling through GITRL after engagement by soluble GITR initiates the immunoregulatory pathway of tryptophan catabolism in mouse plasmacytoid dendritic cells, by means of noncanonical NF-
B–dependent induction of indoleamine 2,3-dioxygenase (IDO). The synthetic glucocorticoid dexamethasone administered in vivo activated IDO through the symmetric induction of GITR in CD4+ T cells and GITRL in plasmacytoid dendritic cells. The drug exerted IDO-dependent protection in a model of allergic airway inflammation. Modulation of tryptophan catabolism via the GITR-GITRL coreceptor system might represent an effective therapeutic target in immune regulation. Induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids.
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06126 Perugia, Italy.
- Department of Clinical and Experimental Medicine, University of Perugia, 06126 Perugia, Italy.
- Bioceros BV, 3584 CM Utrecht, The Netherlands.
- These authors contributed equally to this work.
Correspondence to: Paolo Puccetti1,4 e-mail: plopcc@tin.it
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