Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. van Essen, D., Kikutani, H. & Gray, D. CD40 ligand-transduced co-stimulation of T cells in the development of helper function. Nature 378, 620–623 (1995).

    Article  CAS  Google Scholar 

  2. Eissner, G., Kolch, W. & Scheurich, P. Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev. 15, 353–366 (2004).

    Article  CAS  Google Scholar 

  3. Grohmann, U. et al. CTLA-4–Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097–1101 (2002).

    Article  CAS  Google Scholar 

  4. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

    Article  CAS  Google Scholar 

  5. Orabona, C. et al. CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nat. Immunol. 5, 1134–1142 (2004).

    Article  CAS  Google Scholar 

  6. Mellor, A.L. & Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    Article  CAS  Google Scholar 

  7. Nocentini, G. & Riccardi, C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur. J. Immunol. 35, 1016–1022 (2005).

    Article  CAS  Google Scholar 

  8. Shevach, E.M. & Stephens, G.L. The GITR–GITRL interaction: co-stimulation or contrasuppression of regulatory activity? Nat. Rev. Immunol. 6, 613–618 (2006).

    Article  CAS  Google Scholar 

  9. Nocentini, G. et al. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc. Natl. Acad. Sci. USA 94, 6216–6221 (1997).

    Article  CAS  Google Scholar 

  10. Tone, M. et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc. Natl. Acad. Sci. USA 100, 15059–15064 (2003).

    Article  CAS  Google Scholar 

  11. Kim, J.D. et al. Cloning and characterization of GITR ligand. Genes Immun. 4, 564–569 (2003).

    Article  CAS  Google Scholar 

  12. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).

    Article  CAS  Google Scholar 

  13. Kohm, A.P., Williams, J.S. & Miller, S.D. Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis. J. Immunol. 172, 4686–4690 (2004).

    Article  CAS  Google Scholar 

  14. Stephens, G.L. et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J. Immunol. 173, 5008–5020 (2004).

    Article  CAS  Google Scholar 

  15. Ronchetti, S. et al. GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur. J. Immunol. 34, 613–622 (2004).

    Article  CAS  Google Scholar 

  16. Ko, K. et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J. Exp. Med. 202, 885–891 (2005).

    Article  CAS  Google Scholar 

  17. Seo, S.K. et al. 4–1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med. 10, 1088–1094 (2004).

    Article  CAS  Google Scholar 

  18. Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2, 1144–1150 (2001).

    Article  CAS  Google Scholar 

  19. Colonna, M., Trinchieri, G. & Liu, Y.J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

    Article  CAS  Google Scholar 

  20. Ochando, J.C. et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7, 652–662 (2006).

    Article  CAS  Google Scholar 

  21. Mellor, A.L. et al. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol. 171, 1652–1655 (2003).

    Article  CAS  Google Scholar 

  22. Fallarino, F. et al. Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement. J. Immunol. 173, 3748–3754 (2004).

    Article  CAS  Google Scholar 

  23. Fallarino, F. & Puccetti, P. Toll-like receptor 9-mediated induction of the immunosuppressive pathway of tryptophan catabolism. Eur. J. Immunol. 36, 8–11 (2006).

    Article  CAS  Google Scholar 

  24. Fallarino, F. et al. Ligand and cytokine dependence of the immunosuppressive pathway of tryptophan catabolism in plasmacytoid dendritic cells. Int. Immunol. 17, 1429–1438 (2005).

    Article  CAS  Google Scholar 

  25. Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E. & Prendergast, G.C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319 (2005).

    Article  CAS  Google Scholar 

  26. Lawrence, T., Bebien, M., Liu, G.Y., Nizet, V. & Karin, M. IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434, 1138–1143 (2005).

    Article  CAS  Google Scholar 

  27. Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).

    Article  CAS  Google Scholar 

  28. Kinoshita, D. et al. Essential role of IκB kinase α in thymic organogenesis required for the establishment of self-tolerance. J. Immunol. 176, 3995–4002 (2006).

    Article  CAS  Google Scholar 

  29. Chen, X., Murakami, T., Oppenheim, J.J. & Howard, O.M. Differential response of murine CD4+CD25+ and CD4+CD25 T cells to dexamethasone-induced cell death. Eur. J. Immunol. 34, 859–869 (2004).

    Article  CAS  Google Scholar 

  30. Romani, L. Immunity to fungal infections. Nat. Rev. Immunol. 4, 1–23 (2004).

    Article  Google Scholar 

  31. Judson, M.A. & Stevens, D.A. Current pharmacotherapy of allergic bronchopulmonary aspergillosis. Expert Opin. Pharmacother. 2, 1065–1071 (2001).

    Article  CAS  Google Scholar 

  32. Montagnoli, C. et al. Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism. J. Immunol. 176, 1712–1723 (2006).

    Article  CAS  Google Scholar 

  33. Romani, L. et al. Thymosin α1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood 108, 2265–2274 (2006).

    Article  CAS  Google Scholar 

  34. Romani, L. & Puccetti, P. Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism. Trends Microbiol. 14, 183–189 (2006).

    Article  CAS  Google Scholar 

  35. Bluestone, J.A. & Tang, Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr. Opin. Immunol. 17, 638–642 (2005).

    Article  CAS  Google Scholar 

  36. Grohmann, U., Fallarino, F. & Puccetti, P. Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol. 24, 242–248 (2003).

    Article  CAS  Google Scholar 

  37. Orabona, C. et al. Towards the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood 107, 2846–2854 (2006).

    Article  CAS  Google Scholar 

  38. Gurtner, G.J., Newberry, R.D., Schloemann, S.R., McDonald, K.G. & Stenson, W.F. Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology 125, 1762–1773 (2003).

    Article  CAS  Google Scholar 

  39. Hayashi, T. et al. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J. Clin. Invest. 114, 270–279 (2004).

    Article  CAS  Google Scholar 

  40. de Heer, H.J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).

    Article  CAS  Google Scholar 

  41. Mellor, A.L. et al. Cutting edge: CpG oligonucleotides induce splenic CD19+ dendritic cells to acquire potent indoleamine 2,3-dioxygenase-dependent T cell regulatory functions via IFN type 1 signaling. J. Immunol. 175, 5601–5605 (2005).

    Article  CAS  Google Scholar 

  42. Wingender, G. et al. Systemic application of CpG-rich DNA suppresses adaptive T cell immunity via induction of IDO. Eur. J. Immunol. 36, 12–20 (2006).

    Article  CAS  Google Scholar 

  43. Yang, C.H., Murti, A. & Pfeffer, L.M. Interferon induces NF-κB-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-κB activation to promote cell survival. J. Biol. Chem. 280, 31530–31536 (2005).

    Article  CAS  Google Scholar 

  44. Bonizzi, G. et al. Activation of IKKα target genes depends on recognition of specific κB binding sites by RelB:p52 dimers. EMBO J. 23, 4202–4210 (2004).

    Article  CAS  Google Scholar 

  45. Gilliet, M. & Liu, Y.J. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J. Exp. Med. 195, 695–704 (2002).

    Article  CAS  Google Scholar 

  46. Ito, T. et al. Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J. Exp. Med. 204, 105–115 (2007).

    Article  CAS  Google Scholar 

  47. Hwu, P. et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J. Immunol. 164, 3596–3599 (2000).

    Article  CAS  Google Scholar 

  48. Fallarino, F. et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176, 6752–6761 (2006).

    Article  CAS  Google Scholar 

  49. Karagiannidis, C. et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J. Allergy Clin. Immunol. 114, 1425–1433 (2004).

    Article  CAS  Google Scholar 

  50. Vacca, C. et al. CD40 ligation prevents onset of tolerogenic properties in human dendritic cells treated with CTLA-4-Ig. Microbes Infect. 7, 1040–1048 (2005).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paolo Puccetti.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1563

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing