Skip to main content
SpringerLink
Log in

Indoleamine 2,3-Dioxygenase and Regulatory Function: Tryptophan Starvation and Beyond

  • Protocol
  • First Online:
Suppression and Regulation of Immune Responses

Part of the book series: Methods in Molecular Biology ((MIMB,volume 677))

Abstract

Indoleamine 2,3-dioxygenase (IDO) is an ancestral enzyme that, initially confined to the regulation of tryptophan availability in local tissue microenvironments, is now considered to play a wider role that extends to homeostasis and plasticity of the immune system. Thus, IDO biology has many implications for many aspects of immunopathology, including viral infections, neoplasia, autoimmunity, and chronic inflammation. Its immunoregulatory effects are mainly mediated by dendritic cells (DCs) and involve not only tryptophan deprivation but also production of kynurenines that act on IDO− DCs – thus rendering an otherwise stimulatory DC capable of regulatory effects – as well as on T cells. As a result, IDO+ DCs mediate multiple effects on T lymphocytes, including inhibition of proliferation, apoptosis, and differentiation toward a regulatory phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Yamamoto, S., and Hayaishi, O. (1967) Tryptophan pyrrolase of rabbit intestine. d- and l-tryptophan-cleaving enzyme or enzymes. J. Biol. Chem. 242, 5260–5266.

    PubMed  CAS  Google Scholar 

  2. Taylor, M. W., and Feng, G. S. (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 5, 2516–2522.

    PubMed  CAS  Google Scholar 

  3. Munn, D. H., Zhou, M., Attwood, J. T., et al. (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193.

    Article  PubMed  CAS  Google Scholar 

  4. Sugimoto, H., Oda, S., Otsuki, T., et al. (2006) Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc. Natl. Acad. Sci. U.S.A. 103, 2611–2616.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Macchiarulo, A., Nuti, R., Bellocchi, D., et al. (2007) Molecular docking and spatial coarse graining simulations as tools to investigate substrate recognition, enhancer binding and conformational transitions in indoleamine-2,3-dioxygenase (IDO). Biochim. Biophys. Acta 1774, 1058–1068.

    Article  PubMed  CAS  Google Scholar 

  7. Romani, L., Fallarino, F., De Luca, A., et al. (2008) Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215.

    Article  PubMed  CAS  Google Scholar 

  8. Alegre, E., Lopez, A. S., and Gonzalez, A. (2005) Tryptophan metabolites interfere with the Ehrlich reaction used for the measurement of kynurenine. Anal. Biochem. 339, 188–189.

    Article  PubMed  CAS  Google Scholar 

  9. Belladonna, M. L., Volpi, C., Bianchi, R., et al. (2008) Cutting edge: autocrine TGF-β sustains default tolerogenesis by IDO-competent dendritic cells. J. Immunol. 181, 5194–5198.

    PubMed  CAS  Google Scholar 

  10. Belladonna, M. L., Orabona, C., Grohmann, U., and Puccetti, P. (2009) TGF-β and kynurenines as the key to infectious tolerance. Trends Mol. Med. 15, 41–49.

    Article  PubMed  CAS  Google Scholar 

  11. Ueno, A., Cho, S., Cheng, L., et al. (2007) Transient upregulation of indoleamine 2,3-dioxygenase in dendritic cells by human chorionic gonadotropin downregulates autoimmune diabetes. Diabetes 56, 1686–1693.

    Article  PubMed  CAS  Google Scholar 

  12. Zhu, W. H., Lu, C. Z., Huang, Y. M., et al. (2007) A putative mechanism on remission of multiple sclerosis during pregnancy: estrogen-induced indoleamine 2,3-dioxygenase by dendritic cells. Mult. Scler. 13, 33–40.

    Article  PubMed  CAS  Google Scholar 

  13. von Bergwelt-Baildon, M. S., Popov, A., Saric, T., et al. (2006) CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood 108, 228–237.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Fallarino, F., Grohmann, U., Hwang, K. W., et al. (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Orabona, C., Belladonna, M. L., Vacca, C., et al. (2005) 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.

    PubMed  CAS  Google Scholar 

  19. Grohmann, U., Volpi, C., Fallarino, F., et al. (2007) Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med. 13, 579–586.

    Article  PubMed  CAS  Google Scholar 

  20. Muller, A. J., DuHadaway, J. B., Donover, P. S., et al. (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319.

    Article  PubMed  CAS  Google Scholar 

  21. Orabona, C., Tomasello, E., Fallarino, F., et al. (2005) Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12. Eur. J. Immunol. 35, 3111–3118.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Orabona, C., Pallotta, M. T., Volpi, C., et al. (2008) SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 20828–20833.

    Article  PubMed  CAS  Google Scholar 

  24. Ball, H. J., Yuasa, H. J., Austin, C. J., et al. (2009) Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. Int. J. Biochem. Cell Biol. 41, 467–471.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang, Y., Kang, S. A., Mukherjee, T., et al. (2007) Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis. Biochemistry 46, 145–155.

    Article  PubMed  CAS  Google Scholar 

  26. Löb, S., Königsrainer, A., Schafer, R., et al. (2008) Levo- but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells. Blood 111, 2152–2154.

    Article  PubMed  Google Scholar 

  27. Metz, R., Duhadaway, J. B., Kamasani, U., et al. (2007) 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.

    Article  PubMed  CAS  Google Scholar 

  28. Grohmann, U., Fallarino, F., Bianchi, R., et al. (2003) A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice. J. Exp. Med. 198, 153–160.

    Article  PubMed  CAS  Google Scholar 

  29. Platten, M., Ho, P. P., Youssef, S., et al. (2005) Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 310, 850–855.

    Article  PubMed  CAS  Google Scholar 

  30. Gurtner, G. J., Newberry, R. D., Schloemann, S. R., et al. (2003) Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology 125, 1762–1773.

    Article  PubMed  CAS  Google Scholar 

  31. Seo, S. K., Choi, J. H., Kim, Y. H., et al. (2004) 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med. 10, 1088–1094.

    Article  PubMed  CAS  Google Scholar 

  32. Popov, A., Abdullah, Z., Wickenhauser, C., et al. (2006) Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J. Clin. Invest. 116, 3160–3170.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  34. Uyttenhove, C., Pilotte, L., Theate, I., et al. (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9, 1269–1274.

    Article  PubMed  CAS  Google Scholar 

  35. Munn, D. H., Sharma, M. D., Hou, D., et al. (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290.

    PubMed  CAS  Google Scholar 

  36. Curti, A., Trabanelli, S., Salvestrini, V., et al. (2009) The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood 113, 2394–2401.

    Article  PubMed  CAS  Google Scholar 

  37. Boasso, A., Herbeuval, J. P., Hardy, A. W., et al. (2007) HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 109, 3351–3359.

    Article  PubMed  CAS  Google Scholar 

  38. Prlic, M., and Bevan, M. J. (2009) Immunology: a metabolic switch to memory. Nature 460, 41–42.

    Article  PubMed  CAS  Google Scholar 

  39. Blander, J. M., and Amsen, D. (2009) Immunology. Amino acid addiction. Science 324, 1282–1283.

    Article  PubMed  CAS  Google Scholar 

  40. Sharma, M. D., Hou, D. Y., Liu, Y., et al. (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113, 6102–6111.

    Article  PubMed  CAS  Google Scholar 

  41. Munn, D. H., Sharma, M. D., Baban, B., et al. (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642.

    Article  PubMed  CAS  Google Scholar 

  42. Cobbold, S. P., Adams, E., Farquhar, C. A., et al. (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl. Acad. Sci. U.S.A. 106, 12055–12060.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. Hayashi, T., Mo, J. H., Gong, X., et al. (2007) 3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. Proc. Natl. Acad. Sci. U.S.A. 104, 18619–18624.

    Article  PubMed  CAS  Google Scholar 

  45. Belladonna, M. L., Grohmann, U., Guidetti, P., et al. (2006) Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO. J. Immunol. 177, 130–137.

    PubMed  CAS  Google Scholar 

  46. Fallarino, F., Grohmann, U., You, S., et al. (2006) 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.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  48. Löb, S., Königsrainer, A., Rammensee, H. G., et al. (2009) Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat. Rev. Cancer 9, 445–452.

    Article  PubMed  Google Scholar 

  49. Yen, M. C., Lin, C. C., Chen, Y. L., et al. (2009) A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase. Clin. Cancer Res. 15, 641–649.

    Article  PubMed  CAS  Google Scholar 

  50. Ménard, C., Ghiringhelli, F., Roux, S., et al. (2008) Ctla-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: surrogate marker of efficacy of tremelimumab? Clin. Cancer Res. 14, 5242–5249.

    Article  PubMed  Google Scholar 

  51. Hryniewicz, A., Boasso, A., Edghill-Smith, Y., et al. (2006) CTLA-4 blockade decreases TGF-β, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood 108, 3834–3842.

    Article  PubMed  CAS  Google Scholar 

  52. Fallarino, F., Bianchi, R., Orabona, C., et al. (2004) CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice. J. Exp. Med. 200, 1051–1062.

    Article  PubMed  CAS  Google Scholar 

  53. Fallarino, F., Volpi, C., Zelante, T., et al. (2009) IDO mediates TLR9-driven protection from experimental autoimmune diabetes. J. Immunol. 183, 6303–6312.

    Article  PubMed  CAS  Google Scholar 

  54. Muchamuel, T., Basler, M., Aujay, M. A.,et al. (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 15, 781–787.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The Authors would like to thank Gianluca Andrielli for digital art.

Author information

Authors and Affiliations

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

    Ciriana Orabona & Ursula Grohmann

Authors
  1. Ciriana Orabona
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ursula Grohmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ursula Grohmann .

Editor information

Editors and Affiliations

  1. CHUHotel Dieu, INSERM UMR 643, Bd. Jean Monnet 30, Nantes, 44093, France

    Maria Cristina Cuturi

  2. CHU Hotel Dieu, INSERM UMR 643, Bd. Jean Monnet 30, Nantes, 44093, France

    Ignacio Anegon

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press

About this protocol

Cite this protocol

Orabona, C., Grohmann, U. (2010). Indoleamine 2,3-Dioxygenase and Regulatory Function: Tryptophan Starvation and Beyond. In: Cuturi, M., Anegon, I. (eds) Suppression and Regulation of Immune Responses. Methods in Molecular Biology, vol 677. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-869-0_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-869-0_19

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-868-3

  • Online ISBN: 978-1-60761-869-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation