IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation


The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) suppresses T-cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation. 'Reverse signalling' and 'non-canonical activation' of the transcription factor nuclear factor-κB (NF-κB) characterize the peculiar events that occur in dendritic cells when T-cell-engaged ligands work as signalling receptors and culminate in the induction of IDO expression by dendritic cells in an inhibitor of NF-κB (IκB) kinase-α (IKKα)-dependent manner. In this Opinion article, we propose that IDO acts as a bridge between dendritic cells and CD4+ regulatory T cells, and that regulatory T cells use reverse signalling and non-canonical NF-κB activation for effector function and self-propagation. This mechanism may also underlie the protective function of glucocorticoids in pathological conditions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: A model of crosstalk between dendritic cells and T cells via reverse signalling.
Figure 2: Regulatory T-cell generation via reverse and non-canonical signalling to pDCs.
Figure 3: Non-canonical NF-κB-mediated induction of IDO expression is essential for the maintenance of immune homeostasis in the airways.


  1. 1

    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).

    CAS  PubMed  Google Scholar 

  2. 2

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

    CAS  Google Scholar 

  3. 3

    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).

    CAS  PubMed  Google Scholar 

  4. 4

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

    CAS  Google Scholar 

  5. 5

    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).

    CAS  PubMed  Google Scholar 

  6. 6

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

    CAS  PubMed  Google Scholar 

  7. 7

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

    CAS  PubMed  Google Scholar 

  8. 8

    Du, M. X., Sotero-Esteva, W. D. & Taylor, M. W. Analysis of transcription factors regulating induction of indoleamine 2,3-dioxygenase by IFN-γ. J. Interferon Cytokine Res. 20, 133–142 (2000).

    CAS  PubMed  Google Scholar 

  9. 9

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

    CAS  PubMed  Google Scholar 

  10. 10

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

    CAS  PubMed  Google Scholar 

  11. 11

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Moseman, E. A. et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J. Immunol. 173, 4433–4442 (2004).

    CAS  PubMed  Google Scholar 

  13. 13

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

    CAS  PubMed  Google Scholar 

  14. 14

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

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

    CAS  Google Scholar 

  16. 16

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

    CAS  Google Scholar 

  17. 17

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

    CAS  Google Scholar 

  18. 18

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

    CAS  PubMed  Google Scholar 

  19. 19

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

    CAS  Google Scholar 

  20. 20

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

    CAS  PubMed  Google Scholar 

  21. 21

    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).

    CAS  PubMed  Google Scholar 

  22. 22

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

    CAS  PubMed  Google Scholar 

  23. 23

    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. Nature Med. 11, 312–319 (2005).

    CAS  PubMed  Google Scholar 

  24. 24

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

    CAS  PubMed  Google Scholar 

  25. 25

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Hayden, M. S. & Ghosh, S. Signaling to NF-κB. Genes Dev. 18, 2195–2224 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    CAS  PubMed  Google Scholar 

  28. 28

    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).

    CAS  PubMed  Google Scholar 

  29. 29

    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).

    CAS  PubMed  Google Scholar 

  30. 30

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

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ball, H. J. et al. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 396, 203–213 (2007).

    CAS  PubMed  Google Scholar 

  33. 33

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

    CAS  Google Scholar 

  34. 34

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

    CAS  Google Scholar 

  35. 35

    Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nature Rev. Immunol. 7, 179–190 (2007).

    CAS  Google Scholar 

  36. 36

    Wood, K. J. & Sawitzki, B. Interferon γ: a crucial role in the function of induced regulatory T cells in vivo. Trends Immunol. 27, 183–187 (2006).

    CAS  PubMed  Google Scholar 

  37. 37

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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    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).

    CAS  PubMed  Google Scholar 

  39. 39

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    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).

    CAS  PubMed  Google Scholar 

  41. 41

    Tang, Q. & Bluestone, J. A. Plasmacytoid DCs and Treg cells: casual acquaintance or monogamous relationship? Nature Immunol. 7, 551–553 (2006).

    CAS  Google Scholar 

  42. 42

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

    CAS  PubMed  Google Scholar 

  43. 43

    Manlapat, A. K., Kahler, D. J., Chandler, P. R., Munn, D. H. & Mellor, A. L. Cell-autonomous control of interferon type I expression by indoleamine 2,3-dioxygenase in regulatory CD19+ dendritic cells. Eur. J. Immunol. 37, 1064–1071 (2007).

    CAS  PubMed  Google Scholar 

  44. 44

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

    CAS  PubMed  Google Scholar 

  45. 45

    Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001).

    CAS  Google Scholar 

  46. 46

    Hoebe, K. et al. Genetic analysis of innate immunity. Adv. Immunol. 91, 175–226 (2006).

    CAS  PubMed  Google Scholar 

  47. 47

    Braun, D., Longman, R. S. & Albert, M. L. A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood 106, 2375–2381 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

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

    CAS  PubMed  Google Scholar 

  49. 49

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

    CAS  PubMed  Google Scholar 

  50. 50

    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).

    CAS  Google Scholar 

  51. 51

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Christensen, S. R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428 (2006).

    CAS  PubMed  Google Scholar 

  53. 53

    Lomada, D., Liu, B., Coghlan, L., Hu, Y. & Richie, E. R. Thymus medulla formation and central tolerance are restored in IKKα−/− mice that express an IKKα transgene in keratin 5+ thymic epithelial cells. J. Immunol. 178, 829–837 (2007).

    CAS  PubMed  Google Scholar 

  54. 54

    Lu, L. F., Gondek, D. C., Scott, Z. A. & Noelle, R. J. NFκB-inducing kinase deficiency results in the development of a subset of regulatory T cells, which shows a hyperproliferative activity upon glucocorticoid-induced TNF receptor family-related gene stimulation. J. Immunol. 175, 1651–1657 (2005).

    CAS  PubMed  Google Scholar 

  55. 55

    Curti, A. et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25 into CD25+ T regulatory cells. Blood 109, 2871–2877 (2007).

    CAS  PubMed  Google Scholar 

  56. 56

    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).

    CAS  PubMed  Google Scholar 

  57. 57

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

    CAS  PubMed  Google Scholar 

  58. 58

    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).

    CAS  PubMed  Google Scholar 

  59. 59

    Tas, S. W. et al. Non-canonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 4 May 2007 (doi:10.1182/blood-2006-11-056010).

    CAS  PubMed  Google Scholar 

  60. 60

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

    CAS  Google Scholar 

  61. 61

    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).

    CAS  PubMed  Google Scholar 

  62. 62

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

    CAS  PubMed  Google Scholar 

  63. 63

    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).

    CAS  PubMed  Google Scholar 

  64. 64

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

    CAS  PubMed  Google Scholar 

  65. 65

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

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Munn, D. H. Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation. Curr. Opin. Immunol. 18, 220–225 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    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).

    CAS  PubMed  Google Scholar 

  69. 69

    Santucci, L. et al. GITR modulates innate and adaptive mucosal immunity during the development of experimental colitis in mice. Gut 56, 52–60 (2007).

    CAS  PubMed  Google Scholar 

  70. 70

    Wills-Karp, M., Santeliz, J. & Karp, C. L. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nature Rev. Immunol. 1, 69–75 (2001).

    CAS  Google Scholar 

  71. 71

    Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    PubMed Central  Google Scholar 

  72. 72

    Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    CAS  PubMed  Google Scholar 

  73. 73

    Neish, A. S. et al. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science 289, 1560–1563 (2000).

    CAS  PubMed  Google Scholar 

  74. 74

    Kelly, D. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nature Immunol. 5, 104–112 (2004).

    CAS  Google Scholar 

  75. 75

    Foligne, B. et al. A key role of dendritic cells in probiotic functionality. PLoS ONE 2, e313–e324 (2007).

    PubMed  PubMed Central  Google Scholar 

  76. 76

    Elias, J. A., Zhu, Z., Chupp, G. & Homer, R. J. Airway remodeling in asthma. J. Clin. Invest. 104, 1001–1006 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Padrid, P. A. et al. CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma. Am. J. Respir. Cell Mol. Biol. 18, 453–462 (1998).

    CAS  PubMed  Google Scholar 

  78. 78

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Hayashi, T. & Raz, E. TLR9-based immunotherapy for allergic disease. Am. J. Med. 119, 897.e1–897.e6 (2006).

    Google Scholar 

  80. 80

    De Bosscher, K., Vanden Berghe, W. & Haegeman, G. The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev. 24, 488–522 (2003).

    CAS  PubMed  Google Scholar 

  81. 81

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

    CAS  PubMed  Google Scholar 

  82. 82

    Turck, J., Oberdorfer, C., Vogel, T., Mackenzie, C. R. & Daubener, W. Enhancement of antimicrobial effects by glucocorticoids. Med. Microbiol. Immunol. 194, 47–53 (2005).

    PubMed  Google Scholar 

  83. 83

    Tang, Q. et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J. Immunol. 171, 3348–3352 (2003).

    CAS  PubMed  Google Scholar 

  84. 84

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

    CAS  PubMed  Google Scholar 

  85. 85

    Orabona, C. 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).

    CAS  PubMed  Google Scholar 

  86. 86

    Blasius, A. L. & Colonna, M. Sampling and signaling in plasmacytoid dendritic cells: the potential roles of Siglec-H. Trends Immunol. 27, 255–260 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

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

    CAS  PubMed  Google Scholar 

  88. 88

    Fallarino, F. et al. T cell apoptosis by tryptophan catabolism. Cell. Death Differ. 9, 1069–1077 (2002).

    CAS  PubMed  Google Scholar 

  89. 89

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Sawitzki, B. et al. IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J. Exp. Med. 201, 1925–1935 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Zegarra-Moran, O. et al. Double mechanism for apical tryptophan depletion in polarized human bronchial epithelium. J. Immunol. 173, 542–549 (2004).

    CAS  PubMed  Google Scholar 

  93. 93

    Beutelspacher, S. C. et al. Expression of indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of alloresponses. Am. J. Transplant. 6, 1320–1330 (2006).

    CAS  PubMed  Google Scholar 

  94. 94

    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).

    CAS  PubMed  Google Scholar 

  95. 95

    Zaph, C. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007).

    CAS  PubMed  Google Scholar 

Download references


We thank G. Andrielli for help with the original art work. Support for the work in our laboratory came in part from grants from the Juvenile Diabetes Research Foundation (U.G. and P.P.) and the Italian Association for Cancer Research (P.P.).

Author information



Corresponding author

Correspondence to Paolo Puccetti.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


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