Abstract

Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-β (TGF-β) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.

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References

  1. 1.

    The evolution of self-tolerance: a new cell arises to meet the challenge of self-reactivity. Immunol. Today 19, 448–454 (1998).

  2. 2.

    & Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11, 47–59 (2010).

  3. 3.

    & Control of immune response by amino acid metabolism. Immunol. Rev. 236, 243–264 (2010).

  4. 4.

    Moonlighting proteins–an update. Mol. Biosyst. 5, 345–350 (2009).

  5. 5.

    et al. Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. USA 104, 473–478 (2007).

  6. 6.

    , , , & Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. Int. J. Biochem. Cell Biol. 41, 467–471 (2009).

  7. 7.

    et al. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 67, 7082–7087 (2007).

  8. 8.

    & IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

  9. 9.

    & IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation. Nat. Rev. Immunol. 7, 817–823 (2007).

  10. 10.

    , & Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol. 24, 242–248 (2003).

  11. 11.

    et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).

  12. 12.

    et al. Cutting edge: Autocrine TGF-β sustains default tolerogenesis by IDO-competent dendritic cells. J. Immunol. 181, 5194–5198 (2008).

  13. 13.

    , , & TGF-β and kynurenines as the key to infectious tolerance. Trends Mol. Med. 15, 41–49 (2009).

  14. 14.

    et al. MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity. J. Exp. Med. 207, 1891–1905 (2010).

  15. 15.

    , & Tolerogenic plasmacytoid DC. Eur. J. Immunol. 40, 2667–2676 (2010).

  16. 16.

    & Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses. Ann. NY Acad. Sci. 1183, 89–103 (2010).

  17. 17.

    & Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol. Rev. 234, 142–162 (2010).

  18. 18.

    , , & Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int. Rev. Immunol. 29, 133–155 (2010).

  19. 19.

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

  20. 20.

    et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med. 13, 579–586 (2007).

  21. 21.

    , & The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).

  22. 22.

    & ITAMs versus ITIMs: striking a balance during cell regulation. J. Clin. Invest. 109, 161–168 (2002).

  23. 23.

    & Immune inhibitory receptors. Science 290, 84–89 (2000).

  24. 24.

    et al. Decoding protein-protein interactions through combinatorial chemistry: sequence specificity of SHP-1, SHP-2, and SHIP SH2 domains. Biochemistry 44, 14932–14947 (2005).

  25. 25.

    et al. CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover. Blood 109, 1061–1068 (2007).

  26. 26.

    et al. SOCS3 targets Siglec 7 for proteasomal degradation and blocks Siglec 7-mediated responses. J. Biol. Chem. 282, 3418–3422 (2007).

  27. 27.

    et al. SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc. Natl. Acad. Sci. USA 105, 20828–20833 (2008).

  28. 28.

    , & Insights into Src kinase functions: structural comparisons. Trends Biochem. Sci. 23, 179–184 (1998).

  29. 29.

    , , & Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol. Rev. 224, 11–43 (2008).

  30. 30.

    et al. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat. Immunol. 9, 542–550 (2008).

  31. 31.

    et al. IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9. Nature 440, 949–953 (2006).

  32. 32.

    et al. Noncanonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 110, 1540–1549 (2007).

  33. 33.

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

  34. 34.

    On watching the watchers: IDO and type I/II IFN. Eur. J. Immunol. 37, 876–879 (2007).

  35. 35.

    & Relationship between interferon-γ, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 5, 2516–2522 (1991).

  36. 36.

    et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

  37. 37.

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

  38. 38.

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

  39. 39.

    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).

  40. 40.

    et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

  41. 41.

    et al. Identification of key cytosolic kinases containing evolutionarily conserved kinase tyrosine-based inhibitory motifs (KTIMs). Dev. Comp. Immunol. 34, 481–484 (2010).

  42. 42.

    et al. A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J. Exp. Med. 198, 153–160 (2003).

  43. 43.

    et al. IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J. Immunol. 183, 6303–6312 (2009).

  44. 44.

    et al. Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat. Med. 16, 897–902 (2010).

  45. 45.

    et al. Cutting edge: silencing suppressor of cytokine signaling 3 expression in dendritic cells turns CD28-Ig from immune adjuvant to suppressant. J. Immunol. 174, 6582–6586 (2005).

  46. 46.

    et al. IL-23 neutralization protects mice from Gram-negative endotoxic shock. Cytokine 34, 161–169 (2006).

  47. 47.

    et al. IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. J. Immunol. 168, 5448–5454 (2002).

  48. 48.

    et al. A-MADMAN: annotation-based microarray data meta-analysis tool. BMC Bioinformatics 10, 201–211 (2009).

  49. 49.

    , , , & Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319 (2005).

  50. 50.

    et al. Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation. J. Immunol. 171, 2581–2587 (2003).

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Acknowledgements

We thank G.C. Prendergast (Lankenau Institute for Medical Research) for the mIDOprom900-luc plasmid, and G. Andrielli for digital art and image editing. Supported by the Italian Ministry of Health (GR-2008-1138004 ('Innovative IDO-targeting interventions in autoimmunity') to C.O.), the Associazione per l'Aiuto ai Giovani con Diabete dell'Umbria (U.G.) and Associazione Italiana per la Ricerca sul Cancro (P.P.).

Author information

Author notes

    • Francesca Fallarino
    • , Paolo Puccetti
    •  & Ursula Grohmann

    These authors contributed equally to this work.

Affiliations

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

    • Maria T Pallotta
    • , Ciriana Orabona
    • , Claudia Volpi
    • , Carmine Vacca
    • , Maria L Belladonna
    • , Roberta Bianchi
    • , Mario Calvitti
    • , Maria C Fioretti
    • , Francesca Fallarino
    • , Paolo Puccetti
    •  & Ursula Grohmann
  2. Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.

    • Giuseppe Servillo
    •  & Cinzia Brunacci
  3. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

    • Silvio Bicciato
    •  & Emilia M C Mazza
  4. Bioceros, Utrecht, The Netherlands.

    • Louis Boon
  5. Institute for Research in Biomedicine, Bellinzona, Switzerland.

    • Fabio Grassi

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Contributions

M.T.P. designed and did experiments; C.O., C.Vo. C.Va., M.L.B., R.B., C.B., M.C. and E.M.C.M. did experiments; G.S., S.B. and M.C.F. contributed to experimental design; L.B. and F.G. provided reagents; F.F. designed experiments and supervised research; P.P. supervised research; and U.G. designed experiments, supervised research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ursula Grohmann.

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DOI

https://doi.org/10.1038/ni.2077

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