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Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy

Nature Medicine volume 13, pages 579–586 (2007)Cite this article

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-κB–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.

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Figure 1: Splenic pDCs constitutively express GITRL, which specifically recognizes soluble GITR.
Figure 2: GITRL engagement by GITR-Ig confers suppressive properties on pDCs that require IDO expression and function.
Figure 3: IFN-α dependence of IDO induction in pDCs by GITR-Ig.
Figure 4: GITR-Ig activates noncanonical NF-κB signaling leading to IDO functional expression.
Figure 5: Dexamethasone causes GITR-dependent expression of IDO protein and function.
Figure 6: IDO-dependent effects of dexamethasone in allergic airway inflammation.

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Acknowledgements

We thank P. Mosci for maintaining the mutant strains of mice and performing histopathology; and G. Andrielli for digital art and image editing. Supported by the Italian Association for Cancer Research.

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Author notes

  1. Luigina Romani, Carlo Riccardi and Paolo Puccetti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, 06126, Italy

    Ursula Grohmann, Claudia Volpi, Francesca Fallarino, Silvia Bozza, Roberta Bianchi, Carmine Vacca, Ciriana Orabona, Maria L Belladonna, Francesco Bistoni, Maria C Fioretti, Luigina Romani & Paolo Puccetti

  2. Department of Clinical and Experimental Medicine, University of Perugia, Perugia, 06126, Italy

    Emira Ayroldi, Giuseppe Nocentini & Carlo Riccardi

  3. Bioceros BV, CM Utrecht, 3584, The Netherlands

    Louis Boon

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Supplementary information

Supplementary Fig. 1

GITR-Ig mediates processing of p100 to generate p52. (PDF 171 kb)

Supplementary Fig. 2

Kinetic immunoblot analysis of NIK, IKKα and IKKβ expression in pDCs treated with specific siRNAs (+) in one experiment representative of three. (PDF 196 kb)

Supplementary Fig. 3

NIK and IKKα are required for IFN-α induction by GITR-Ig. (PDF 21 kb)

Supplementary Fig. 4

Dexamethasone in vivo up-regulates GITR and GITRL. (PDF 83 kb)

Supplementary Fig. 5

Cytokine production in vitro in response to a range of GITR-Ig concentrations by pDCs from mice treated or not with dexamethasone (dex). (PDF 23 kb)

Supplementary Fig. 6

GITR-Ig activates noncanonical NF-κB signaling in Ifnar−/− mice. (PDF 242 kb)

Supplementary Methods (PDF 139 kb)

Supplementary Note (PDF 197 kb)

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Grohmann, U., Volpi, C., Fallarino, F. et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 13, 579–586 (2007). https://doi.org/10.1038/nm1563

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