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.

  • Review Article
  • Published:

Ido expression by dendritic cells: tolerance and tryptophan catabolism

Key Points

  • The peripheral immune system can promote either immunity or tolerance when presented with new antigens. Dendritic cells (DCs) have a crucial role in determining immune outcomes by acquiring antigens, collating environmental cues and then becoming cells that are either potent stimulators or suppressors of T-cell responses.

  • Enzymatic activity of indoleamine 2,3-dioxygenase (IDO) correlates with reduced T-cell-mediated responses in several experimental (mouse) systems, including models of autoimmune diseases, cancer, organ and tissue transplant rejection, and pregnancy.

  • IDO is a haeme-containing enzyme that catabolizes compounds containing indole rings, such as the essential amino acid tryptophan. IDO protein is encoded by a tightly regulated gene that is responsive to inflammatory mediators in a limited range of cell types.

  • Mature DCs that express functional IDO enzyme activity can be potent suppressors of T-cell responses in vivo and in vitro.

  • Ligation of CD80/CD86 molecules, which are normally thought of as co-stimulatory molecules on DCs, induces the expression of functional IDO by certain subsets of DCs (IDO-competent DCs); other DC subsets, and other antigen-presenting cell types that express CD80/CD86 do not express IDO after CD80/CD86 ligation.

  • The synthetic immunomodulatory reagent cytotoxic T lymphocyte antigen 4 (CTLA4)–immunoglobulin fusion protein is a potent inducer of IDO expression by DCs.

  • Regulatory T cells that express CTLA4 induce IDO-competent DCs to express IDO, indicating that CTLA4+ regulatory T cells use the IDO mechanism to suppress T-cell responses and promote tolerance.

  • More speculatively, IDO-expressing DCs might promote the development of regulatory T cells; if so, regulatory T cells and IDO-competent DCs might cooperate to form a self-amplifying immunoregulatory network.

Abstract

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pivotal role of dendritic cells in deciding tolerance versus immunity.
Figure 2: Indoleamine 2,3-dioxygenase molecular genetics and enzyme activity.
Figure 3: Maturation of indoleamine 2,3-dioxygenase-competent dendritic cells.
Figure 4: Potential downstream mechanisms of indoleamine 2,3-dioxygenase.

Similar content being viewed by others

References

  1. Uhlig, H. H. & Powrie, F. Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses. J. Clin. Invest. 112, 648–651 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sotomayor, E. M. et al. Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood 98, 1070–1077 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Moser, M. Dendritic cells in immunity and tolerance — do they display opposite functions? Immunity 19, 5–8 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Hackstein, H. & Thomson, A. W. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nature Rev. Immunol. 4, 24–34 (2004).

    Article  CAS  Google Scholar 

  5. Mosmann, T. R. & Livingstone, A. M. Dendritic cells: the immune information management experts. Nature Immunol. 5, 564–566 (2004).

    Article  CAS  Google Scholar 

  6. Bendelac, A. & Medzhitov, R. Adjuvants of immunity: harnessing innate immunity to promote adaptive immunity. J. Exp. Med. 195, F19–F23 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Medzhitov, R. & Janeway, C. A., Jr. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Probst, H. C., Lagnel, J., Kollias, G. & van den Broek, M. Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity 18, 713–720 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen, W., Frank, M. E., Jin, W. & Wahl, S. M. TGF-β released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14, 715–725 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Powrie, F. & Maloy, K. J. Immunology. Regulating the regulators. Science 299, 1030–1031 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Fairchild, P. J. & Waldmann, H. Dendritic cells and prospects for transplantation tolerance. Curr. Opin. Immunol. 12, 528–535 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Mellor, A. L. & Munn, D. H. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol. Today 20, 469–473 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998). This report shows that IDO activity inhibits a T-cell-mediated process in mice; in this case maternal T-cell immunity to fetal alloantigens during pregnancy.

    Article  CAS  PubMed  Google Scholar 

  17. Mellor, A. L., Keskin, D. B., Johnson, T., Chandler, P. & Munn, D. H. Cells expressing indoleamine 2,3 dioxygenase inhibit T cell responses. J. Immunol. 168, 3771–3776 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Friberg, M. et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101, 151–155 (2002). References 18 and 19 show that IDO activity can suppress antitumour immunity, challenging previous notions that IDO activity is exclusively an innate host defence mechanism against tumours.

    Article  CAS  PubMed  Google Scholar 

  19. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med. 9, 1269–1274 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Munn, D. H. et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290 (2004). This report identifies specific DC subsets in mice that express IDO, accumulate in tumour-draining lymph nodes and mediate potent T-cell suppression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grohmann, U. et al. CTLA-4–Ig regulates tryptophan catabolism in vivo. Nature Immunol. 3, 1097–1101 (2002). This paper indicates that ligation of CD80/CD86 is an alternative mechanism to induce functional IDO-expression by mouse DCs and showed that a component of CTLA4–immunoglobulin-mediated inhibition of allograft rejection was IDO dependent.

    Article  CAS  Google Scholar 

  23. Sakurai, K., Zou, J., Tschetter, J., Ward, J. & Shearer, G. Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 129, 186–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. 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  PubMed  Google Scholar 

  25. Swanson, K. A., Zheng, Y., Heidler, K. M., Mizobuchi, T. & Wilkes, D. S. CD11c+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase. Am. J. Respir. Cell Mol. Biol. 30, 311–318 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Stone, T. W. & Darlington, L. G. Endogenous kynurenines as targets for drug discovery and development. Nature Rev. Drug Discov. 1, 609–620 (2002).

    Article  CAS  Google Scholar 

  29. Suzuki, T. et al. Comparison of the sequences of Turbo and Sulculus indoleamine dioxygenase-like myoglobin genes. Gene 308, 89–94 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Dai, W. & Gupta, S. L. Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-γ. J. Biol. Chem. 265, 19871–19877 (1990).

    CAS  PubMed  Google Scholar 

  31. Hassanain, H. H., Chon, S. Y. & Gupta, S. L. Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-γ and -α. Analysis of the regulatory region of the gene and identification of an interferon-γ-inducible DNA-binding factor. J. Biol. Chem. 268, 5077–5084 (1993).

    CAS  PubMed  Google Scholar 

  32. Burke, F., Knowles, R. G., East, N. & Balkwill, F. R. The role of indoleamine 2,3-dioxygenase in the anti-tumour activity of human interferon-γ in vivo. Int. J. Cancer 60, 115–122 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Varga, J., Yufit, T., Hitraya, E. & Brown, R. R. Control of extracellular matrix degradation by interferon-γ. The tryptophan connection. Adv. Exp. Med. Biol. 398, 143–148 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999). This report identifies tryptophan depletion due to IDO upregulation in human macrophages as a mechanism to inhibit T cell proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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). These authors show that human DCs also mediate IDO-dependent T-cell suppression.

    Article  CAS  PubMed  Google Scholar 

  36. Chon, S. Y., Hassanain, H. H. & Gupta, S. L. Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in intereron-γ-inducible expression of human indoleamine 2,3-dioxygenase gene. J. Biol. Chem. 271, 17247–17252 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Silva, N. M. et al. Expression of indoleamine 2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with Toxoplasma gondii: induction by endogenous γ interferon and requirement of interferon regulatory factor 1. Infect. Immun. 70, 859–868 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Babcock, T. A. & Carlin, J. M. Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor α in interferon-treated epithelial cells. Cytokine 12, 588–594 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Robinson, C. M., Shirey, K. A. & Carlin, J. M. Synergistic transcriptional activation of indoleamine dioxygenase by IFN-γ and tumor necrosis factor-α. J. Interferon Cytokine Res. 23, 413–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Fujigaki, S. et al. Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-γ-independent mechanism. Eur. J. Immunol. 31, 2313–2318 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Yuan, W., Collado-Hidalgo, A., Yufit, T., Taylor, M. & Varga, J. Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-β: selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression. J. Cell. Physiol. 177, 174–186 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. MacKenzie, C. R., Gonzalez, R. G., Kniep, E., Roch, S. & Daubener, W. Cytokine mediated regulation of interferon-γ-induced IDO activation. Adv. Exp. Med. Biol. 467, 533–539 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol. 4, 1206–1212 (2003). This report shows that T cells expressing CTLA4 induce IDO expression by DCs.

    Article  CAS  Google Scholar 

  44. 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). This paper shows that specific DC subsets in mouse spleens mediate dominant IDO-dependent T-cell suppression in vivo following ligation of CD80/CD86.

    Article  CAS  PubMed  Google Scholar 

  45. Munn, D. H., Sharma, M. D. & Mellor, A. L. Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J. Immunol. 172, 4100–4110 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Mellor, A. L. et al. Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int. Immunol. (doi:10.93/intimm/dxh140). In this report, the T-cell-regulatory functions of certain cloned CD4+CD25+ T cells are shown to depend on their ability to induce functional IDO expression by specific DC subsets from mouse spleens through CD80/CD86 ligation.

  47. Finger, E. B. & Bluestone, J. A. When ligand becomes receptor — tolerance via B7 signaling on DCs. Nature Immunol. 3, 1056–1057 (2002).

    Article  CAS  Google Scholar 

  48. Kudo, Y., Boyd, C. A., Sargent, I. L. & Redman, C. W. Tryptophan degradation by human placental indoleamine 2,3-dioxygenase regulates lymphocyte proliferation. J. Physiol. 535, 207–215 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kudo, Y. & Boyd, C. A. Human placental indoleamine 2,3-dioxygenase: cellular localization and characterization of an enzyme preventing fetal rejection. Biochim. Biophys. Acta 1500, 119–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Kudo, Y. et al. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. J. Reprod. Immunol. 61, 87–98 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Honig, A. et al. Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno–fetal tolerance. J. Reprod. Immunol. 61, 79–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Baban, B. et al. Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J. Reprod. Immunol. 61, 67–77 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Mackler, A. M., Barber, E. M., Takikawa, O. & Pollard, J. W. Indoleamine 2,3-dioxygenase is regulated by IFN-γ in the mouse placenta during Listeria monocytogenes infection. J. Immunol. 170, 823–830 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Takikawa, O., Yoshida, R., Kido, R. & Hayaishi, O. Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J. Biol. Chem. 261, 3648–3653 (1986).

    CAS  PubMed  Google Scholar 

  55. Yoshida, R. et al. Regulation of indoleamine 2,3-dioxygenase activity in the small intestine and the epididymis of mice. Arch. Biochem. Biophys. 203, 343–351 (1980).

    Article  CAS  PubMed  Google Scholar 

  56. Yoshida, R., Urade, Y., Nakata, K., Watanabe, Y. & Hayashi, O. Specific induction of indoleamine 2,3-dioxygenase by bacterial lipopolysaccharide in the mouse lung. Arch. Biochem. Biophys. 212, 629–637 (1981).

    Article  CAS  PubMed  Google Scholar 

  57. Fallarino, F. et al. Functional expression of indoleamine 2,3-dioxygenase by murine CD8α+ dendritic cells. Int. Immunol. 14, 65–68 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Thomas, S. R. et al. Antioxidants inhibit indoleamine 2,3-dioxygenase in IFN-γ-activated human macrophages: posttranslational regulation by pyrrolidine dithiocarbamate. J. Immunol. 166, 6332–6340 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Aitken, J. B. et al. Determination of the nature of the heme environment in nitrosyl indoleamine 2,3-dioxygenase using multiple-scattering analyses of X-ray absorption fine structure. Biochemistry 43, 4892–4898 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Hucke, C., Mackenzie, C. R., Adjogble, K. D. Z., Takikawa, O. & Daubener, W. Nitric oxide-mediated regulation of γ-interferon-induced bacteriosis: inhibition of degradation of human indoleamine 2,3-dioxygenase. Infect. Immun. 72, 2723–2730 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pfefferkorn, E. R. Interferon-γ blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc. Natl Acad. Sci. USA 81, 908–912 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Carlin, J. M., Borden, E. C., Sondel, P. M. & Byrne, G. I. Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes. J. Leukoc. Biol. 45, 29–34 (1989).

    Article  CAS  PubMed  Google Scholar 

  63. Gupta, S. L. et al. Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts. Infect. Immun. 62, 2277–2284 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. MacKenzie, C. R., Hadding, U. & Daubener, W. Interferon-γ-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. J. Infect. Dis. 178, 875–878 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Hayashi, T. et al. Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase. Infect. Immun. 69, 6156–6164 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bodaghi, B. et al. Role of IFN-γ-induced indoleamine 2,3 dioxygenase and inducible nitric oxide synthase in the replication of human cytomegalovirus in retinal pigment epithelial cells. J. Immunol. 162, 957–964 (1999).

    CAS  PubMed  Google Scholar 

  67. Adams, O. et al. Role of indoleamine-2,3-dioxygenase in α/β and γ-interferon-mediated antiviral effects against herpes simplex virus infections. J. Virol. 78, 2632–2636 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fujigaki, S. et al. L-tryptophan-L-kynurenine pathway metabolism accelerated by Toxoplasma gondii infection is abolished in γ-interferon-gene-deficient mice: cross-regulation between inducible nitric oxide synthase and indoleamine-2,3-dioxygenase. Infect. Immun. 70, 779–786 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rottenberg, M. E. et al. Regulation and role of IFN-γ in the innate resistance to infection with Chlamydia pneumoniae. J. Immunol. 164, 4812–4818 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Widner, B., Weiss, G. & Fuchs, D. Tryptophan degradation to control T-cell responsiveness. Immunol. Today 21, 250 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Rogers, K. A. et al. Type 1 and type 2 responses to Leishmania major. FEMS Microbiol. Lett. 209, 1–7 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Cady, S. G. & Sono, M. 1-methyl-DL-tryptophan, β-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys. 291, 326–333 (1991).

    Article  CAS  PubMed  Google Scholar 

  73. Mellor, A. L. et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nature Immunol. 2, 64–68 (2001).

    Article  CAS  Google Scholar 

  74. Alexander, A. M. et al. Indoleamine 2,3-dioxygenase expression in transplanted NOD islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes 51, 356–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Munn, D. H. et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Summers, K. L., Hock, B. D., McKenzie, J. L. & Hart, D. N. Phenotypic characterization of five dendritic cell subsets in human tonsils. Am. J. Pathol. 159, 285–295 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rissoan, M. C. et al. Subtractive hybridization reveals the expression of immunoglobulin-like transcript 7, Eph-B1, granzyme B, and 3 novel transcripts in human plasmacytoid dendritic cells. Blood 100, 3295–3303 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Grohmann, U. et al. IFN-γ inhibits presentation of a tumor/self peptide by CD8α dendritic cells via potentiation of the CD8α+ subset. J. Immunol. 165, 1357–1363 (2000). This report identifies IDO as a mechanism used by mouse regulatory DCs.

    Article  CAS  PubMed  Google Scholar 

  79. Grohmann, U. et al. CD40 ligation ablates the tolerogenic potential of lymphoid dendritic cells. J. Immunol. 166, 277–283 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Grohmann, U. et al. IL-6 inhibits the tolerogenic function of CD8α+ dendritic cells expressing indoleamine 2,3-dioxygenase. J. Immunol. 167, 708–714 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Grohmann, U. et al. Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation. J. Immunol. 171, 2581–2587 (2003). This report shows that IDO-mediated suppression can be upregulated or downregulated by signals from the immune system.

    Article  CAS  PubMed  Google Scholar 

  82. O'Keeffe, M. et al. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8+ dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307–1319 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Martin, P. et al. Characterization of a new subpopulation of mouse CD8α+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100, 383–390 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Regulatory T cells mediate maternal tolerance to the fetus. Nature Immunol. 5, 266–271 (2004).

    Article  CAS  Google Scholar 

  85. Barcelo-Batllori, S. et al. Proteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases. Proteomics 2, 551–560 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Varga, J., Yufit, T. & Brown, R. R. Inhibition of collagenase and stromelysin gene expression by interferon-γ in human dermal fibroblasts is mediated in part via induction of tryptophan degradation. J. Clin. Invest. 96, 475–481 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Meisel, R. et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103, 4619–4621 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. von Bubnoff, D. et al. FcεRI induces the tryptophan degradation pathway involved in regulating T cell responses. J. Immunol. 169, 1810–1816 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Lee, G. K. et al. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107, 452–460 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fallarino, F. et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 9, 1069–1077 (2002). This report indicates that certain T cells are sensitive to the toxic effects of tryptophan metabolites that can be produced by cells expressing IDO.

    Article  CAS  PubMed  Google Scholar 

  91. Frumento, G. et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196, 459–468 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Terness, P. et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J. Exp. Med. 196, 447–457 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Seman, M. et al. NAD-induced T cell death: ADP-ribosylation of cell surface proteins by ART2 activates the cytolytic P2X7 purinoceptor. Immunity 19, 571–582 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Moffett, J. R. & Namboodiri, M. A. Tryptophan and the immune response. Immunol. Cell Biol. 81, 247–265 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, P. et al. The GCN2 eIF2α kinase is required for adaptation to amino acid deprivation in mice. Mol. Cell. Biol. 22, 6681–6688 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Rohde, J., Heitman, J. & Cardenas, M. E. The TOR kinases link nutrient sensing to cell growth. J. Biol. Chem. 276, 9583–9586 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biol. 4, 699–704 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Marshall, B., Keskin, D. B. & Mellor, A. L. Regulation of prostaglandin synthesis and cell adhesion by a tryptophan catabolizing enzyme. BMC Biochem. 2, 5 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. van Wissen, M., Snoek, M., Smids, B., Jansen, H. M. & Lutter, R. IFN-γ amplifies IL-6 and IL-8 responses by airway epithelial-like cells via indoleamine 2,3-dioxygenase. J. Immunol. 169, 7039–7044 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Li, Y., Tredget, E. E. & Ghahary, A. Cell surface expression of MHC class I antigen is suppressed in indoleamine 2,3-dioxygenase genetically modified keratinocytes: implications in allogeneic skin substitute engraftment. Hum. Immunol. 65, 114–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Waldmann, H. & Cobbold, S. Exploiting tolerance processes in transplantation. Science 305, 209–212 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Munn, D. H. & Mellor, A. L. Macrophages and the regulation of self-reactive T cells. Curr. Pharm. Des. 9, 257–264 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Parekh, V. V. et al. B cells activated by lipopolysaccharide, but not by anti-Ig and anti-CD40 antibody, induce anergy in CD8+ T cells: role of TGF-β1. J. Immunol. 170, 5897–5911 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nature Immunol. 3, 944–950 (2002).

    Article  CAS  Google Scholar 

  106. Mahnke, K., Qian, Y., Knop, J. & Enk, A. H. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101, 4862–4869 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Bilsborough, J., George, T. C., Norment, A. & Viney, J. L. Mucosal CD8α+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108, 481–492 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wakkach, A. et al. Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 18, 605–617 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Faunce, D. E., Terajewicz, A. & Stein-Streilein, J. Cutting edge: in vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis. J. Immunol. 172, 1991–1995 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. 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  PubMed  PubMed Central  Google Scholar 

  111. Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).

    Article  CAS  Google Scholar 

  112. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  113. Bilsborough, J. & Viney, J. L. Getting to the guts of immune regulation. Immunology 106, 139–143 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang, H. Y. et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20, 107–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  116. Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Logan, G. J. et al. HeLa cells cocultured with peripheral blood lymphocytes acquire an immuno-inhibitory phenotype through upregulation of indoleamine 2,3-dioxygenase activity. Immunology 105, 478–487 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Huang, A. Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–965 (1994).

    Article  CAS  PubMed  Google Scholar 

  119. Spiotto, M. T. et al. Increasing tumor antigen expression overcomes 'ignorance' to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity 17, 737–747 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Lee, J. R. et al. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab. Invest. 83, 1457–1466 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Hartmann, E. et al. Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. 63, 6478–6487 (2003).

    CAS  PubMed  Google Scholar 

  122. Vermi, W. et al. Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J. Pathol. 200, 255–268 (2003).

    Article  PubMed  Google Scholar 

  123. Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nature Med. 7, 1339–1346 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Grant, R. S. et al. Induction of indoleamine 2,3-dioxygenase in primary human macrophages by human immunodeficiency virus type 1 is strain dependent. J. Virol. 74, 4110–4115 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Burudi, E. M. et al. Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency virus-infected monkey brains. J. Virol. 76, 12233–12241 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Heyes, M. P. et al. Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. FASEB J. 12, 881–896 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Kerr, S. J. et al. Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages. Neurology 49, 1671–1681 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Fuchs, D. et al. Immune activation and decreased tryptophan in patients with HIV-1 infection. J. Interferon Res. 10, 599–603 (1990).

    Article  CAS  PubMed  Google Scholar 

  129. Zangerle, R. et al. Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection. Clin. Immunol. 104, 242–247 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Garber, K. Make or break for co-stimulatory blockers. Nature Biotechnol. 22, 145–147 (2004).

    Article  CAS  Google Scholar 

  131. Kremer, J. M. et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4–Ig. N. Engl. J. Med. 349, 1907–1915 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Waldmann, H. & Cobbold, S. Regulating the immune response to transplants. A role for CD4+ regulatory cells? Immunity 14, 399–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Frolova, L. Y., Grigorieva, A. Y., Sudomoina, M. A. & Kisselev, L. L. The human gene encoding tryptophanyl-tRNA synthetase: interferon-response elements and exon–intron organization. Gene 128, 237–245 (1993).

    Article  CAS  PubMed  Google Scholar 

  134. Fleckner, J., Martensen, P. M., Tolstrup, A. B., Kjeldgaard, N. O. & Justesen, J. Differential regulation of the human, interferon inducible tryptophanyl-tRNA synthetase by various cytokines in cell lines. Cytokine 7, 70–77 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Tatsumi, K. et al. Induction of tryptophan 2,3-dioxygenase in the mouse endometrium during implantation. Biochem. Biophys. Res. Commun. 274, 166–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Suzuki, S. et al. Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti. Biochem. J. 355, 425–429 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Werner-Felmayer, G. et al. Characteristics of interferon induced tryptophan metabolism in human cells in vitro. Biochim. Biophys. Acta 1012, 140–147 (1989).

    Article  CAS  PubMed  Google Scholar 

  138. Ottaviani, E. & Franceschi, C. The invertebrate phagocytic immunocyte:clues to a common evolution of immune and neuroendocrine systems. Immunol. Today 18, 169–174 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Guilbert, L., Robertson, S. A. & Wegmann, T. G. The trophoblast as an integral component of a macrophage-cytokine network. Immunol. Cell Biol. 71, 49–57 (1993).

    Article  CAS  PubMed  Google Scholar 

  140. Guleria, I. & Pollard, J. W. The trophoblast is a component of the innate immune system during pregnancy. Nature Med. 6, 589–593 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Grolleau, A. et al. Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J. Biol. Chem. 277, 22175–22184 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Calkhoven, C. F., Muller, C. & Leutz, A. Translational control of gene expression and disease. Trends Mol. Med. 8, 577–583 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Garcia-Sanz, J. A., Mikulits, W., Livingstone, A., Lefkovits, I. & Mullner, E. W. Translational control: a general mechanism for gene regulation during T cell activation. FASEB J. 12, 299–306 (1998).

    Article  CAS  PubMed  Google Scholar 

  145. Chiarugi, A., Rovida, E., Dello Sbarba, P. & Moroni, F. Tryptophan availability selectively limits NO-synthase induction in macrophages. J. Leukoc. Biol. 73, 172–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Mahnke, K., Knop, J. & Enk, A. H. Induction of tolerogenic DCs: 'you are what you eat'. Trends Immunol. 24, 646–651 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Ridge, J. P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Alpan, O., Bachelder, E., Isil, E., Arnheiter, H. & Matzinger, P. 'Educated' dendritic cells act as messengers from memory to naive T helper cells. Nature Immunol. 5, 615–622 (2004).

    Article  CAS  Google Scholar 

  149. Thomas, S. R. & Stocker, R. Antioxidant activities and redox regulation of interferon-γ-induced tryptophan metabolism in human monocytes and macrophages. Adv. Exp. Med. Biol. 467, 541–552 (1999).

    Article  CAS  PubMed  Google Scholar 

  150. Mellor, A. L. & Munn, D. H. Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses. J. Reprod. Immunol. 52, 5–13 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Miki, T. et al. Blockade of tryptophan catabolism prevents spontaneous tolerogenicity of liver allografts. Transplant. Proc. 33, 129–130 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the National Institutes of Health for supporting the research described in this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrew L. Mellor.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

CD8α

CD80

CD86

CTLA4

GCN2

IDO

IFN-γ

IL-1

IL-10

IRF1

mTOR

STAT1

TDO

TGF-β

TNF

Glossary

ANTIGENICITY

The ability to be recognized by the immune system by binding to T- and B-cell receptors, although this might not result in overt immune responses.

IMMUNOGENICITY

The ability to provoke overt immune responses.

ESSENTIAL AMINO ACIDS

Amino acids that cannot be synthesized by cells and must be acquired in the diet. Tryptophan is energetically unfavourable to synthesize and even organisms that can synthesize tryptophan will take it up in preference to synthesizing it.

APOENZYME

The protein component of an enzyme that requires additional co-factors to become active (holoenzyme).

TROPHOBLAST GIANT CELLS

(TGCs). Cells of fetal origin in mouse extra-embryonic tissues that develop into large cells through marked amplification of DNA content coupled with cytoplasmic expansion. Primary TGCs line the outer surfaces of the fetal–placental unit at midgestation in mice. Secondary TGCs migrate into the maternal deciduas at later times during mouse gestation.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin antigen or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

GRAFT-VERSUS-HOST-DISEASE

(GVHD). An immune response mounted against the recipient of an allograft by immunocompetent T cells that are derived from the graft. Typically, it is seen in the context of allogeneic bone-marrow transplantation.

NITRIC OXIDE SYNTHASE

An inducible haeme-containing enzyme that produces nitric oxide in response to inflammatory signals.

LINKED SUPPRESSION

The phenomenon of suppressing responses to a specific antigen by co-presenting it simultaneously with another antigen, against which tolerance has previously been established.

INFECTIOUS TOLERANCE

The ability of a tolerized population of T cells to induce tolerance in a new, naive population of T cells. Tolerance might be to the same antigens or to new antigens that are encountered in the same context (linked suppression). Newly tolerized T cells can, in turn, induce tolerance of other T cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mellor, A., Munn, D. Ido expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4, 762–774 (2004). https://doi.org/10.1038/nri1457

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1457

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