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.

  • Opinion
  • Published:

Creating immune privilege: active local suppression that benefits friends, but protects foes

An Erratum to this article was published on 01 February 2008

Abstract

Natural regulatory mechanisms prevent inappropriate immune activation to self and innocuous foreign antigens. Here, we adapt the notion of immune privilege, which was originally applied to transplanted tissues, to consider how antigenic tumour cells and chronic pathogens might exploit natural regulatory mechanisms to become non-immunogenic. This conceptual approach reveals new mechanistic perspectives that may help to explain the paradoxical persistence of tumours and chronic pathogens, and suggests new opportunities to improve immunotherapy to treat these chronic inflammatory diseases.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Immunogenic and non-immunogenic responses to antigenic stimuli.
Figure 2: Potential regulatory checkpoints that create and maintain immune privilege in local tissue microenvironments.
Figure 3: Regulatory APCs may suppress T-cell responses by inducing metabolic stress in naive and TReg cells that respond to antigen.

Similar content being viewed by others

References

  1. Parmiani, G., De Filippo, A., Novellino, L. & Castelli, C. Unique human tumor antigens: immunobiology and use in clinical trials. J. Immunol. 178, 1975–1979 (2007).

    Article  CAS  Google Scholar 

  2. Simpson, E. A historical perspective on immunological privilege. Immunol. Rev. 213, 12–22 (2006).

    Article  Google Scholar 

  3. Caspi, R. R. Ocular autoimmunity: the price of privilege? Immunol. Rev. 213, 23–35 (2006).

    Article  Google Scholar 

  4. Niederkorn, J. Y. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nature Immunol. 7, 354–359 (2006).

    Article  CAS  Google Scholar 

  5. Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D. & Ploix, C. C. CNS immune privilege: hiding in plain sight. Immunol. Rev. 213, 48–65 (2006).

    Article  Google Scholar 

  6. Fijak, M. & Meinhardt, A. The testis in immune privilege. Immunol. Rev. 213, 66–81 (2006).

    Article  CAS  Google Scholar 

  7. Medawar, P. B. Some immunological and endocrinological problems raised by evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7, 320–328 (1953).

    Google Scholar 

  8. Waldmann, H. et al. Regulatory T cells and organ transplantation. Semin. Immunol. 16, 119–126 (2004).

    Article  CAS  Google Scholar 

  9. Tafuri, A., Alferink, J., Moller, P., Hammerling, G. J. & Arnold, B. T cell awareness of paternal alloantigens during pregnancy. Science 270, 630–633 (1995).

    Article  CAS  Google Scholar 

  10. Jiang, S. P. & Vacchio, M. S. Multiple mechanisms of peripheral T cell tolerance to the fetal “allograft”. J. Immunol. 160, 3086–3090 (1998).

    CAS  PubMed  Google Scholar 

  11. Zhou, M. & Mellor, A. L. Expanded cohorts of maternal CD8+ T cells specific for paternal MHC class I accumulate during pregnancy. J. Repro. Immunol. 40, 47–62 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. 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 

  14. 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 

  15. Crispe, I. N. et al. Cellular and molecular mechanisms of liver tolerance. Immunol. Rev. 213, 101–118 (2006).

    Article  Google Scholar 

  16. Green, E. A., Choi, Y. & Flavell, R. A. Pancreatic lymph node-derived CD4+CD25+ Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 16, 183–191 (2002).

    Article  CAS  Google Scholar 

  17. Samy, E. T., Parker, L. A., Sharp, C. P. & Tung, K. S. Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node. J. Exp. Med. 202, 771–781 (2005).

    Article  CAS  Google Scholar 

  18. Kraal, G., Samsom, J. N. & Mebius, R. E. The importance of regional lymph nodes for mucosal tolerance. Immunol. Rev. 213, 119–130 (2006).

    Article  Google Scholar 

  19. Loser, K. et al. IL-10 controls ultraviolet-induced carcinogenesis in mice. J. Immunol. 179, 365–371 (2007).

    Article  CAS  Google Scholar 

  20. Iweala, O. I. & Nagler, C. R. Immune privilege in the gut: the establishment and maintenance of nonresponsiveness to dietary antigens and commensal flora. Immunol. Rev. 213, 82–100 (2006).

    Article  Google Scholar 

  21. Matzinger, P. Friendly and dangerous signals: is the tissue in control? Nature Immunol. 8, 11–3 (2007).

    Article  CAS  Google Scholar 

  22. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  Google Scholar 

  23. 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  Google Scholar 

  24. Sansonetti, P. J. & Di Santo, J. P. Debugging how bacteria manipulate the immune response. Immunity 26, 149–161 (2007).

    Article  CAS  Google Scholar 

  25. 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 

  26. 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 

  27. Reis e Sousa, C. Dendritic cells in a mature age. Nature Rev. Immunol. 6, 476–483 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    Article  CAS  Google Scholar 

  30. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nature Rev. Immunol. 5, 641–654 (2005).

    Article  CAS  Google Scholar 

  33. Okazaki, T. & Honjo, T. The PD-1–PD-L pathway in immunological tolerance. Trends Immunol. 27, 195–201 (2006).

    Article  CAS  Google Scholar 

  34. Ferguson, T. A. & Griffith, T. S. A vision of cell death: FasL and immune privilege — 10 years later. Immunol. Rev. 213, 228–238 (2006).

    Article  CAS  Google Scholar 

  35. Keir, M. E., Francisco, L. M. & Sharpe, A. H. PD-1 and its ligands in T-cell immunity. Curr. Opin. Immunol. 19, 309–314 (2007).

    Article  CAS  Google Scholar 

  36. 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).

    Article  CAS  Google Scholar 

  37. 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, 1–10 (2005).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  39. Sharma, M. D. et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 1–13 (2007).

    Article  Google Scholar 

  40. Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2007).

    Article  CAS  Google Scholar 

  41. Morelli, A. E. & Thomson, A. W. Tolerogenic dendritic cells and the quest for transplant tolerance. Nature Rev. Immunol. 7, 610–621 (2007).

    Article  CAS  Google Scholar 

  42. Mahnke, K., Johnson, T. S., Ring, S. & Enk, A. H. Tolerogenic dendritic cells and regulatory T cells: a two-way relationship. J. Dermatol. Sci. 46, 159–167 (2007).

    Article  CAS  Google Scholar 

  43. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Suffia, I. J., Reckling, S. K., Piccirillo, C. A., Goldszmid, R. S. & Belkaid, Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 203, 777–788 (2006).

    Article  CAS  Google Scholar 

  46. Zhou, F., Rouse, B. T. & Huang, L. Induction of cytotoxic T lymphocytes in vivo with protein antigen entrapped in membranous vehicles. J. Immunol. 149, 1599–1604 (1992).

    CAS  PubMed  Google Scholar 

  47. Zhou, G. & Levitsky, H. I. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J. Immunol. 178, 2155–2162 (2007).

    Article  CAS  Google Scholar 

  48. Cobbold, S. P. et al. Immune privilege induced by regulatory T cells in transplantation tolerance. Immunol. Rev. 213, 239–255 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. Rudensky, A. Y. & Campbell, D. J. In vivo sites and cellular mechanisms of T reg cell-mediated suppression. J. Exp. Med. 203, 489–492 (2006).

    Article  CAS  Google Scholar 

  51. Dunn, G. P., Old, L. J. & Schreiber, R. D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004).

    Article  CAS  Google Scholar 

  52. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    Article  CAS  Google Scholar 

  53. Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Rev. Immunol. 4, 941–952 (2004).

    Article  CAS  Google Scholar 

  54. Munn, D. H. & Mellor, A. L. Tumor draining lymph nodes as a site of tolerance induction. Immunol. Rev. 213, 146–158 (2006).

    Article  Google Scholar 

  55. van der Most, R. G., Currie, A., Robinson, B. W. & Lake, R. A. Cranking the immunologic engine with chemotherapy: using context to drive tumor antigen cross-presentation towards useful antitumor immunity. Cancer Res. 66, 601–604 (2006).

    Article  CAS  Google Scholar 

  56. Zhou, G., Drake, C. G. & Levitsky, H. I. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107, 628–636 (2006).

    Article  CAS  Google Scholar 

  57. Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nature Med. 13, 828–835 (2007).

    Article  CAS  Google Scholar 

  58. Gajewski, T. F. et al. Immune resistance orchestrated by the tumor microenvironment. Immunol. Rev. 213, 131–145 (2006).

    Article  CAS  Google Scholar 

  59. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nature Rev. Immunol. 6, 295–307 (2006).

    Article  CAS  Google Scholar 

  60. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007).

    Article  CAS  Google Scholar 

  61. Zhang, B. et al. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J. Exp. Med. 204, 49–55 (2007).

    Article  CAS  Google Scholar 

  62. Peters, N. & Sacks, D. Immune privilege in sites of chronic infection: Leishmania and regulatory T cells. Immunol. Rev. 213, 159–179 (2006).

    Article  CAS  Google Scholar 

  63. Trinchieri, G. Interleukin-10 production by effector T cells: Th1 cells show self control. J. Exp. Med. 204, 239–243 (2007).

    Article  CAS  Google Scholar 

  64. Belkaid, Y. et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 194, 1497–1506 (2001).

    Article  CAS  Google Scholar 

  65. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

    Article  CAS  Google Scholar 

  66. Yurchenko, E. et al. CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J. Exp. Med. 203, 2451–2460 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  68. 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  Google Scholar 

  69. 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).

    Article  CAS  Google Scholar 

  70. Manlapat, A. M., 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).

    Article  CAS  Google Scholar 

  71. Fallarino, F., Gizzi, S., Mosci, P., Grohmann, U. & Puccetti, P. Tryptophan catabolism in IDO+ plasmacytoid dendritic cells. Curr. Drug Metab. 8, 209–216 (2007).

    Article  CAS  Google Scholar 

  72. Chambers, C. A., Kuhns, M. S., Egen, J. G. & Allison, J. P. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol. 19, 565–594 (2001).

    Article  CAS  Google Scholar 

  73. Miyara, M. & Sakaguchi, S. Natural regulatory T cells: mechanisms of suppression. Trends Mol. Med. 13, 108–116 (2007).

    Article  CAS  Google Scholar 

  74. Nowak, M. & Stein-Streilein, J. Invariant NKT cells and tolerance. Int. Rev. Immunol. 26, 95–119 (2007).

    Article  CAS  Google Scholar 

  75. Mizoguchi, A. & Bhan, A. K. A case for regulatory B cells. J. Immunol. 176, 705–710 (2006).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

Mellor, A. L. & Munn, D. H. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nature Reviews Immunology 8, 74–80 (2008)

The authors have intellectual property interests in the therapeutic use of IDO and IDO inhibitors and receive consulting income from NewLink Genetics Inc.

Related links

FURTHER INFORMATION

Andrew Mellor's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mellor, A., Munn, D. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol 8, 74–80 (2008). https://doi.org/10.1038/nri2233

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2233

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