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:

Regulatory lymphocytes

Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity

Nature Reviews Immunology volume 3, pages 211–222 (2003)Cite this article

Key Points

  • Invariant CD1D-restricted T cells (iNKT cells) function during innate and adaptive immunity and regulate many immune responses, such as autoimmune disease, tumour surveillance, infectious disease and abortions.

  • The function of iNKT cells is disease and stage specific. iNKT cells can inhibit or augment pathology.

  • The molecular basis of their functions and the nature of disease-associated iNKT-cell defects are unclear and have been the subject of recent controversy.

  • iNKT cells can be segregated into CD4+ and CD4−CD8− double-negative subsets, which might have distinct functions.

  • During the onset of an inflammatory response, the homeostatic tissue distribution of iNKT cells is altered. After activation, iNKT cells are recruited rapidly and specifically to site(s) of inflammation. These homing responses are controlled, in part, by the expression of specific chemokines and chemokine receptors.

  • ;Dysfunction and changes in the frequency of iNKT cells have been correlated with the development of autoimmunity — in particular, in autoimmune type 1 diabetes in rodents and humans.

  • Activation of iNKT cells in vivo prevents experimental allergic encephalomyelitis (EAE) in some strains of susceptible mice, but is only protective when given at, or before, the onset of disease. Moreover, activation of iNKT cells can exacerbate EAE in a strain- and disease-course-dependent manner.

  • iNKT cells have a crucial role in tumour surveillance and the control of tumour metastasis. The anti-tumour effect depends on direct interactions between iNKT cells and dendritic cells, followed by the activation of natural killer cells and cytotoxic T lymphocytes (CTLs).

  • By contrast, immune surveillance and CTL-mediated destruction of some tumours can be suppressed by iNKT cells by interleukin-13- and STAT6-dependent pathways.

  • Common mechanisms might underlie the development of both tumour immunity and autoimmunity.

  • Despite the potentially beneficial role that iNKT cells might have in the prevention of a given autoimmune disease and certain types of cancer, the mechanisms by which iNKT cells exert their immunoregulatory functions are largely unknown and require further examination before the use of iNKT-cell-based therapies in humans.

Abstract

Invariant CD1D-restricted natural killer T (iNKT) cells function during innate and adaptive immunity and regulate numerous immune responses, such as autoimmune disease, tumour surveillance, infectious disease and abortions. However, the molecular basis of their functions and the nature of disease-associated defects of iNKT cells are unclear and have been the subject of recent controversy. Here, we review recent findings that underscore the potential importance of interactions between iNKT cells and dendritic cells (DCs) that indicate that iNKT cells regulate DC activity to shape both pro-inflammatory and tolerogenic immune responses. The ability to modulate iNKT-cell activity in vivo using the ligand α-galactosylceramide and to treat patients with autoimmune disease or cancer is evaluated also.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: A model of iNKT-cell activation and function.
Figure 2: A model of how tissue damage and chemokines lead to the recruitment of iNKT cells to sites of inflammation.
Figure 3: INKT-cell-mediated tumour rejection.
Figure 4: Hypothetical model of iNKT-cell-mediated regulation of DC maturation in autoimmune diabetes.

Similar content being viewed by others

References

  1. Porcelli, S. A. & Modlin, R. L. The CD1 system: antigen-presenting molecules for T-cell recognition of lipids and glycolipids. Annu. Rev. Immunol. 17, 297–329 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Brossay, L. & Kronenberg, M. Highly conserved antigen-presenting function of CD1d molecules. Immunogenetics 50, 146–151 (1999).

    CAS  PubMed  Google Scholar 

  3. Koseki, H., Imai, K., Ichikawa, T., Hayata, I. & Taniguchi, M. Predominant use of a particular α-chain in suppressor T-cell hybridomas specific for keyhole limpet hemocyanin. Int. Immunol. 1, 557–564 (1989).

    CAS  PubMed  Google Scholar 

  4. Balk, S. P. et al. Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes. Science 253, 1411–1415 (1991).

    CAS  PubMed  Google Scholar 

  5. Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T-cell antigen receptor (TCR) expression by human peripheral blood CD4−8− αβ T cells demonstrates preferential use of several Vβ genes and an invariant TCR α-chain. J. Exp. Med. 178, 1–16 (1993).

    CAS  PubMed  Google Scholar 

  6. Singh, N. et al. Cutting edge: activation of NK T cells by CD1d and α-galactosylceramide directs conventional T cells to the acquisition of a TH2 phenotype. J. Immunol. 163, 2373–2377 (1999).

    CAS  PubMed  Google Scholar 

  7. Bendelac, A. et al. CD1 recognition by mouse NK1.1+ T lymphocytes. Science 268, 863–865 (1995). In this study, the mouse CD1d protein was identified as the restricting element for invariant natural killer T (iNKT) cells.

    CAS  PubMed  Google Scholar 

  8. Godfrey, D. I. et al. NKT cells: facts, functions and fallacies. Immunol. Today 21, 573–583 (2000).

    CAS  PubMed  Google Scholar 

  9. Kronenberg, M. & Gapin, L. The unconventional lifestyle of NKT cells. Nature Rev. Immunol. 2, 557–568 (2002).

    Article  CAS  Google Scholar 

  10. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997). This paper describes how synthetic α-galactosyl ceramides (α-GalCer) were discovered as the first known antigens for iNKT cells.

    CAS  PubMed  Google Scholar 

  11. Gumperz, J. E., Miyake, S., Yamamura, T. & Brenner, M. B. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J. Exp. Med. 195, 625–636 (2002). Together with reference 12, this study showed that when examined ex vivo , CD4+ iNKT cells preferentially secrete T H 2-like cytokines compared with double-negative (DN) iNKT cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, P. T., Benlagha, K., Teyton, L. & Bendelac, A. Distinct functional lineages of human Vα24 natural killer T cells. J. Exp. Med. 195, 637–641 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Delovitch, T. L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Bach, J. F. & Chatenoud, L. Tolerance to islet autoantigens in type 1 diabetes. Annu. Rev. Immunol. 19, 131–161 (2001).

    CAS  PubMed  Google Scholar 

  15. Bendelac, A., Rivera, M. N., Park, H. -S. & Roark, J. H. Mouse CD1-specific NK1 T cells: development, specificity and function. Annu. Rev. Immunol. 15, 535–562 (1997).

    CAS  PubMed  Google Scholar 

  16. Bendelac, A., Hunziker, R. D. & Lantz, O. Increased interleukin-4 and immunoglobulin-E production in transgenic mice overexpressing NK1 T cells. J. Exp. Med. 184, 1285–1293 (1996).

    CAS  PubMed  Google Scholar 

  17. Wilson, S. B. et al. Multiple differences in gene expression in regulatory Vα24JαQ T cells from identical twins discordant for type I diabetes. Proc. Natl Acad. Sci. USA 97, 7411–7416 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang, O. O. et al. CD1d on myeloid dendritic cells stimulates cytokine secretion and cytolytic activity of Vα24JαQ T cells: a feedback mechanism for immune regulation. J. Immunol. 165, 3756–3762 (2000).

    CAS  PubMed  Google Scholar 

  19. Wilson, S. B. & Byrne, M. C. Gene expression in NKT cells: defining a functionally distinct CD1d-restricted T-cell subset. Curr. Opin. Immunol. 13, 555–561 (2001).

    CAS  PubMed  Google Scholar 

  20. Smiley, S. T., Kaplan, M. H. & Grusby, M. J. Immunoglobulin-E production in the absence of interleukin-4-secreting CD1-dependent cells. Science 275, 977–979 (1997). This study showed that T H 2-cell responses can be generated in the absence of CD1d.

    CAS  PubMed  Google Scholar 

  21. Noben-Trauth, N. et al. An interleukin-4 (IL-4)-independent pathway for CD4+ T-cell IL-4 production is revealed in IL-4 receptor-deficient mice. Proc. Natl Acad. Sci. USA 94, 10838–10843 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Eberl, G. et al. Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells. J. Immunol. 162, 6410–6419 (1999).

    CAS  PubMed  Google Scholar 

  23. Matsuda, J. L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000). This study was the first to show iNKT-cell responses ex vivo using CD1d tetramers loaded with α-GalCer.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Matsuda, J. L. et al. Homeostasis of Vα14i NKT cells. Nature Immunol. 3, 966–974 (2002).

    CAS  Google Scholar 

  25. Sharif, S. et al. Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nature Med. 7, 1057–1062 (2001). Together with references 26, 40 and 41, this study showed the protective effect of α-GalCer in non-obese diabetic (NOD) mice.

    CAS  PubMed  Google Scholar 

  26. Naumov, Y. N. et al. Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic-cell subsets. Proc. Natl Acad. Sci. USA 98, 13838–13843 (2001). This study showed that the protective effect of α-GalCer therapy in NOD mice was, in part, due to the recruitment of tolerogenic dendritic cells (DCs) to the pancreatic lymph nodes.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Nieuwenhuis, E. E. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nature Med. 8, 588–593 (2002). This study showed the importance of iNKT cells and monocytes for the acute control of infections in the lung.

    CAS  PubMed  Google Scholar 

  28. Apostolou, I. et al. Murine natural killer T (NKT) cells contribute to the granulomatous reaction caused by mycobacterial cell walls. Proc. Natl Acad. Sci. USA 96, 5141–5146 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kita, H. et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 123, 1031–1043 (2002).

    CAS  PubMed  Google Scholar 

  30. Kim, C. H., Johnston, B. & Butcher, E. C. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Vα24+Vβ11+ NKT-cell subsets with distinct cytokine-producing capacity. Blood 100, 11–16 (2002). This study identified preferential chemokine-receptor expression by human CD4+ and DN iNKT cells.

    CAS  PubMed  Google Scholar 

  31. Faunce, D. E., Sonoda, K. H. & Stein-Streilein, J. MIP-2 recruits NKT cells to the spleen during tolerance induction. J. Immunol. 166, 313–321 (2001).

    CAS  PubMed  Google Scholar 

  32. Sharif, S., Arreaza, G. A., Zucker, P., Mi, Q. S. & Delovitch, T. L. Regulation of autoimmune disease by natural killer T cells. J. Mol. Med. 80, 290–300 (2002).

    CAS  PubMed  Google Scholar 

  33. Cameron, M. J. et al. Differential expression of CC-chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes. J. Immunol. 165, 1102–1110 (2000).

    CAS  PubMed  Google Scholar 

  34. Gombert, J. M. et al. Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse. Eur. J. Immunol. 26, 2989–2998 (1996). This report was the first demonstration of decreased frequency and loss of function of iNKT cells in NOD mice.

    CAS  PubMed  Google Scholar 

  35. Falcone, M. et al. A defect in interleukin-12-induced activation and interferon-γ secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus. J. Exp. Med. 190, 963–972 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wilson, S. B. et al. Extreme TH1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 391, 177–181 (1998). This report was the first demonstration of decreased frequency and loss of function of iNKT cells in humans with insulin-dependent diabetes mellitus.

    CAS  PubMed  Google Scholar 

  37. Mieza, M. A. et al. Selective reduction of Vα14+ NK T cells associated with disease development in autoimmune-prone mice. J. Immunol. 156, 4035–4040 (1996).

    CAS  PubMed  Google Scholar 

  38. Kukreja, A. et al. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109, 131–140 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Baxter, A. G. et al. Association between αβTCR+CD4−CD8− T-cell deficiency and IDDM in NOD/Lt mice. Diabetes 46, 572–582 (1997).

    CAS  PubMed  Google Scholar 

  40. Wang, B., Geng, Y. B. & Wang, C. R. Cd1-restricted NKT cells protect nonobese diabetic mice from developing diabetes. J. Exp. Med. 194, 313–320 (2001). Together with references 26 and 50, this study showed an exacerbation of autoimmune diabetes in CD1d-deficient NOD mice.

    PubMed  PubMed Central  Google Scholar 

  41. Hong, S. et al. The natural killer T-cell ligand α-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nature Med. 7, 1052–1056 (2001).

    CAS  PubMed  Google Scholar 

  42. Mempel, M. et al. Comparison of the T-cell patterns in leprous and cutaneous sarcoid granulomas. Presence of Vα24-invariant natural killer T cells in T-cell-reactive leprosy together with a highly biased T-cell receptor Vα repertoire. Am. J. Pathol. 157, 509–523 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Grattan, M., Mi, Q. S., Meagher, C. & Delovitch, T. L. Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci. Diabetes 51, 215–223 (2002).

    CAS  PubMed  Google Scholar 

  44. Lee, P. T. et al. Testing the NKT-cell hypothesis of human IDDM pathogenesis. J. Clin. Invest. 110, 793–800 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Oikawa, Y. et al. High frequency of Vα24+Vβ11+ T cells observed in type 1 diabetes. Diabetes Care 25, 1818–1823 (2002).

    PubMed  Google Scholar 

  46. Chatenoud, L. Do NKT cells control autoimmunity? J. Clin. Invest. 110, 747–748 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hammond, K. I. L. et al. αβ T-cell receptor (TCR)+CD4−CD8− (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J. Exp. Med. 187, 1047–1056 (1998). This study showed the importance of iNKT cells, IL-4 and IL-10 for protecting NOD mice from autoimmune diabetes by transfer of iNKT cells into naive pre-diabetic NOD mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lehuen, A. et al. Overexpression of natural killer T cells protects Vα14–Jα281 transgenic nonobese diabetic mice against diabetes. J. Exp. Med. 188, 1831–1839 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gombert, J. M. et al. IL-7 reverses NK1+ T-cell-defective IL-4 production in the non-obese diabetic mouse. Int. Immunol. 8, 1751–1758 (1996).

    CAS  PubMed  Google Scholar 

  50. Shi, F. D. et al. Germ-line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc. Natl Acad. Sci. USA 98, 6777–6782 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Beaudoin, L. et al. NKT cells inhibit the onset of diabetes by impairing the development of pathogenic T cells specific for pancreatic β-cells. Immunity 17, 725–736 (2002). This study showed an important contribution of iNKT cells to the inhibition of pathogenic islet-specific T cells.

    CAS  PubMed  Google Scholar 

  52. Sumida, T. et al. Selective reduction of T cells bearing invariant Vα24JαQ antigen receptor in patients with systemic sclerosis. J. Exp. Med. 182, 1163–1168 (1995). This early study was the first to show a paucity of iNKT cells in a human autoimmune disorder.

    CAS  PubMed  Google Scholar 

  53. Yoshimoto, T., Bendelac, A., Hu-Li, J. & Paul, W. Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin-4. Proc. Natl Acad. Sci. USA 92, 11931–11934 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Illes, Z. et al. Differential expression of NKT cell Vα24JαQ invariant TCR chains in the lesions of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J. Immunol. 164, 4375–4381 (2000).

    CAS  PubMed  Google Scholar 

  55. van der Vliet, H. J. et al. Circulating Vα24+Vβ11+ NKT cell numbers are decreased in a wide variety of diseases that are characterized by autoreactive tissue damage. Clin. Immunol. 100, 144–148 (2001).

    CAS  PubMed  Google Scholar 

  56. Zeng, D., Lee, M. K., Tung, J., Brendolan, A. & Strober, S. Cutting edge: a role for CD1 in the pathogenesis of lupus in NZB/NZW mice. J. Immunol. 164, 5000–5004 (2000).

    CAS  PubMed  Google Scholar 

  57. Nagane, Y., Utsugisawa, K., Obara, D. & Tohgi, H. NKT-associated markers and perforin in hyperplastic thymuses from patients with myasthenia gravis. Muscle Nerve 24, 1359–1364 (2001).

    CAS  PubMed  Google Scholar 

  58. Saubermann, L. J. et al. Activation of natural killer T cells by α-galactosylceramide in the presence of CD1d provides protection against colitis in mice. Gastroenterology 119, 119–128 (2000).

    CAS  PubMed  Google Scholar 

  59. Singh, A. K. et al. Natural killer T-cell activation protects mice against experimental autoimmune encephalomyelitis. J. Exp. Med. 194, 1801–1811 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jahng, A. W. et al. Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis. J. Exp. Med. 194, 1789–1799 (2001). This study showed the Janus nature of iNKT cells in experimental allergic encephalomyelitis (EAE).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Pal, E. et al. Costimulation-dependent modulation of experimental autoimmune encephalomyelitis by ligand stimulation of Vα14 NK T cells. J. Immunol. 166, 662–668 (2001).

    CAS  PubMed  Google Scholar 

  62. Miyamoto, K., Miyake, S. & Yamamura, T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 413, 531–534 (2001). This study identified the dependence of protection from EAE on IL-4, potent effects of structural analogues on the T H -cell phenotype of iNKT cells and the adaptive immune response.

    CAS  PubMed  Google Scholar 

  63. Hayakawa, Y. et al. Differential regulation of TH1 and TH2 functions of NKT cells by CD28 and CD40 costimulatory pathways. J. Immunol. 166, 6012–6018 (2001).

    CAS  PubMed  Google Scholar 

  64. Cui, J. et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).

    CAS  PubMed  Google Scholar 

  65. Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000). This study showed the importance of iNKT cells for the surveillance of subsets of endogenously occurring tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kitamura, H. et al. The natural killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J. Exp. Med. 189, 1121–1128 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Tomura, M. et al. A novel function of Vα14+CD4+ NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system. J. Immunol. 163, 93–101 (1999).

    CAS  PubMed  Google Scholar 

  68. Smyth, M. J. et al. Sequential production of interferon-γ by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of α-galactosylceramide. Blood 99, 1259–1266 (2002). This study dissected the temporal requirements for IFN-γ, iNKT cells, DCs and NK cells for tumour surveillance.

    CAS  PubMed  Google Scholar 

  69. Crowe, N. Y., Smyth, M. J. & Godfrey, D. I. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J. Exp. Med. 196, 119–127 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Carnaud, C. et al. Cutting edge. Cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J. Immunol. 163, 4647–4650 (1999).

    CAS  PubMed  Google Scholar 

  71. Fernandez, N. C. et al. Dendritic cells directly trigger NK-cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nature Med. 5, 405–411 (1999).

    CAS  PubMed  Google Scholar 

  72. Terabe, M. et al. NKT-cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R–STAT6 pathway. Nature Immunol. 1, 515–520 (2000). This study showed the inhibitory role that iNKT cells can sometimes have during tumour surveillance.

    CAS  Google Scholar 

  73. Tahir, S. M. et al. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J. Immunol. 167, 4046–4050 (2001). This study showed the loss of, and the development of, a T H 2-cell-like phenotype by iNKT cells in patients with prostate cancer.

    CAS  PubMed  Google Scholar 

  74. Ludewig, B. et al. Immunotherapy with dendritic cells directed against tumor antigens shared with normal host cells results in severe autoimmune disease. J. Exp. Med. 191, 795–804 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Pittet, M. J. et al. High frequencies of naive Melan-A/MART-1-specific CD8+ T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals. J. Exp. Med. 190, 705–715 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Mach, N. et al. Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte–macrophage colony-stimulating factor or Flt3-ligand. Cancer Res. 60, 3239–3246 (2000).

    CAS  PubMed  Google Scholar 

  77. Mathis, D., Vence, L. & Benoist, C. β-cell death during progression to diabetes. Nature 414, 792–798 (2001).

    CAS  PubMed  Google Scholar 

  78. Hoglund, P. et al. Initiation of autoimmune diabetes by developmentally regulated presentation of islet-cell antigens in the pancreatic lymph nodes. J. Exp. Med. 189, 331–339 (1999). This study showed the importance of regional lymph-node antigen presentation for the development of autoimmune diabetes in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Green, E. A. & Flavell, R. A. The temporal importance of TNF-α expression in the development of diabetes. Immunity 12, 459–469 (2000). This study showed the importance of inflammatory cytokine secretion and rate of cell death in promoting autoimmune diabetes in mice.

    CAS  PubMed  Google Scholar 

  80. Sauter, B. et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–434 (2000). This study showed that the development of DC effector function depends on the nature of the cell that a DC encounters.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Steinman, R. M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Steinman, R. M. & Nussenzweig, M. C. Inaugural article. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T-cell tolerance. Proc. Natl Acad. Sci. USA 99, 351–358 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Clare-Salzler, M. J., Brooks, J., Chai, A., Van Herle, K. & Anderson, C. Prevention of diabetes in nonobese diabetic mice by dendritic-cell transfer. J. Clin. Invest. 90, 741–748 (1992). This was the first study to show the protective effect of myeloid DCs derived from the pancreatic lymph nodes in NOD mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Johnson, E. A., Silveira, P., Chapman, H. D., Leiter, E. H. & Serreze, D. V. Inhibition of autoimmune diabetes in nonobese diabetic mice by transgenic restoration of H2-E MHC class II expression: additive, but unequal, involvement of multiple APC subtypes. J. Immunol. 167, 2404–2410 (2001).

    CAS  PubMed  Google Scholar 

  86. Dhodapkar, M. V., Steinman, R. M., Krasovsky, J., Munz, C. & Bhardwaj, N. Antigen-specific inhibition of effector T-cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Albert, M. L., Jegathesan, M. & Darnell, R. B. Dendritic-cell maturation is required for the cross-tolerization of CD8+ T cells. Nature Immunol. 2, 1010–1017 (2001).

    CAS  Google Scholar 

  88. Menges, M. et al. Repetitive injections of dendritic cells matured with tumor-necrosis factor-α induce antigen-specific protection of mice from autoimmunity. J. Exp. Med. 195, 15–21 (2002). This study showed the tolerogenic function of DCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    CAS  PubMed  Google Scholar 

  90. Pulendran, B., Palucka, K. & Banchereau, J. Sensing pathogens and tuning immune responses. Science 293, 253–256 (2001).

    CAS  PubMed  Google Scholar 

  91. Rissoan, M. C. et al. Reciprocal control of T helper cell and dendritic-cell differentiation. Science 283, 1183–1186 (1999). This study showed T H 1- and T H 2-promoting effector functions for human myeloid and lymphoid DCs, respectively.

    CAS  PubMed  Google Scholar 

  92. Liu, Y. J., Kanzler, H., Soumelis, V. & Gilliet, M. Dendritic-cell lineage, plasticity and cross-regulation. Nature Immunol. 2, 585–589 (2001).

    CAS  Google Scholar 

  93. Shreedhar, V. et al. Dendritic cells require T cells for functional maturation in vivo. Immunity 11, 625–636 (1999). This study showed the importance of continued T-cell–DC cross-talk for DC survival.

    CAS  PubMed  Google Scholar 

  94. Vincent, M. S. et al. CD1-dependent dendritic-cell instruction. Nature Immunol. 3, 1163–1168 (2002).

    CAS  Google Scholar 

  95. Kadowaki, N. et al. Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells. J. Exp. Med. 193, 1221–1226 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ikarashi, Y. et al. Dendritic-cell maturation overrules H-2D-mediated natural killer T (NKT) cell inhibition: critical role for B7 in CD1d-dependent NKT cell interferon-γ production. J. Exp. Med. 194, 1179–1186 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Leslie, D. S. et al. CD1-mediated γδ T-cell maturation of dendritic cells. J. Exp. Med. 196, 1575–1584 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Mi, Q. -S., Meagher, C. & Delovitch, T. L. in Novartis Foundation Symposium 252. Generation and Effector Functions of Regulatory Lymphocytes (Wiley, Europe) (in the press).

  99. Cruikshank, W. W., Kornfeld, H. & Center, D. M. Interleukin-16. J. Leukocyte Biol. 67, 757–766 (2000).

    CAS  PubMed  Google Scholar 

  100. Mars, L. T. et al. Vα14–Jα281 NKT cells naturally regulate experimental autoimmune encephalomyelitis in nonobese diabetic mice. J. Immunol. 168, 6007–6011 (2002).

    CAS  PubMed  Google Scholar 

  101. Sonoda, K. H. et al. CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site. J. Exp. Med. 190, 1215–1226 (1999). This study showed the importance of iNKT cells and myeloid antigen-presenting cells expressing CD1d for the generation of antigen-specific tolerance.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Sonoda, K. H. et al. NK T-cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance. J. Immunol. 166, 42–50 (2001).

    CAS  PubMed  Google Scholar 

  103. Takahashi, K., Honeyman, M. C. & Harrison, L. C. Impaired yield, phenotype and function of monocyte-derived dendritic cells in humans at risk for insulin-dependent diabetes. J. Immunol. 161, 2629–2635 (1998).

    CAS  PubMed  Google Scholar 

  104. Serreze, D. V., Gaskins, H. R. & Leiter, E. H. Defects in the differentiation and function of antigen-presenting cells in NOD/Lt mice. J. Immunol. 150, 2534–2543 (1993).

    CAS  PubMed  Google Scholar 

  105. King, C. et al. Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses. Nature Med. 7, 206–214 (2001).

    CAS  PubMed  Google Scholar 

  106. O'Hara, R. M. Jr, Henderson, S. L. & Nagelin, A. Prevention of a TH1 disease by a TH1 cytokine: IL-12 and diabetes in NOD mice. Ann. NY Acad. Sci. 795, 241–249 (1996).

    CAS  PubMed  Google Scholar 

  107. Alleva, D. G. et al. Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-α and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice. Diabetes 49, 1106–1115 (2000).

    CAS  PubMed  Google Scholar 

  108. Poligone, B. et al. Elevated NF-κB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function. J. Immunol. 168, 188–196 (2002).

    CAS  PubMed  Google Scholar 

  109. Osman, Y. et al. Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. Eur. J. Immunol. 30, 1919–1928 (2000).

    CAS  PubMed  Google Scholar 

  110. Giaccone, G. et al. A Phase I study of the NKT-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin. Cancer Res. 8, 3702–3709 (2002).

    CAS  PubMed  Google Scholar 

  111. Okai, M. et al. Human peripheral blood Vα24+Vβ11+ NKT cells expand following administration of α-galactosylceramide-pulsed dendritic cells. Vox. Sang. 83, 250–253 (2002).

    CAS  PubMed  Google Scholar 

  112. Heller, F. et al. Oxazolone colitis, a TH2 colitis model resembling ulcerative colitis is mediated by IL-13-producing NK-T cells. Immunity 17, 629–638 (2002).

    CAS  PubMed  Google Scholar 

  113. Fujii, S. -I., Shimizu, K., Kronenberg, M. & Steinman, R. M. Prolonged interferon-γ-producing NKT response induced with α-galactosylceramide-loaded DCs. Nature Immunol. 3, 867–874 (2002).

    CAS  Google Scholar 

Download references

Acknowledgements

S.B.W. is supported by grants from the National Institutes of Health. T.L.D. is supported by grants from the JDRF, CIHR, ORDCF and LHSC.

Author information

Authors and Affiliations

  1. Diabetes Laboratories, Massachusetts General Hospital, 65 Landsdowne Street, Room 525, Cambridge, 02138, Massachusetts, USA

    S. Brian Wilson

  2. Departments of Microbiology and Immunology, Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, and Medicine, University of Western Ontario, London, N6G 2S6, Ontario, Canada

    Terry L. Delovitch

Authors
  1. S. Brian Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terry L. Delovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terry L. Delovitch.

Related links

Related links

DATABASES

LocusLink

CCL3

CCL4

CCL17

CCL21

CCL24

CCR1

CCR2

CCR3

CCR4

CCR5

CCR6

CCR7

CD1D

CD25

CD40

CD62L

CD80

CD86

CXCL2

CXCL8

CXCL9

CXCL10

CXCL12

CXCR3

CXCR4

CXCR5

CXCR6

GM-CSF

IFN-γ

IL-2

IL-4

IL-7

IL-10

IL-12

IL-13

IL-16

MBP

MOG

NK1.1

perforin

TNF

OMIM

Coeliac disease

Graves disease

multiple sclerosis

myasthenia gravis

primary biliary cirrhosis

psoriasis

rheumatoid arthritis

Sjogren syndrome

SLE

type 1 diabetes

ulcerative colitis

Glossary

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

(EAE). Inflammation of the brain and spinal cord that is generally induced by the administration of myelin basic protein or myelin oligodendrocyte glycoprotein and adjuvants to disease-susceptible strains of mice.

T HELPER 1/2

(TH1/TH2). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce IFN-γ, lymphotoxin and TNF, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoral immunity and downregulate TH1 responses.

NON-OBESE DIABETIC MICE

(NOD mice). These mice spontaneously develop a form of autoimmune diabetes that shares many genetic, immunological and pathological features with the human disease insulin-dependent diabetes mellitus. These mice are the most widely studied animal model of experimental autoimmune disease.

INTROGRESSION

By a process of genetic backcrossing, DNA from a chromosomal segment of one mouse strain is inserted into the homologous region of another mouse strain.

MYELOID DENDRITIC CELLS

Dendritic cells that develop from myeloid, as opposed to lymphoid, precursors and that express cell-surface markers that are characteristic of the myeloid lineage.

VITILIGO

A depigmenting disorder of the skin caused by the destruction of melanocytes that produce cutaneous pigments.

TOLEROGENIC DENDRITIC CELLS

Dendritic cells that can attenuate T-cell-mediated immune responses by deleting, anergizing or changing the effector function of antigen-specific T cells.

ANTERIOR-CHAMBER-ASSOCIATED IMMUNE DEVIATION

(ACAID). Systemic antigen-specific tolerance that develops after inoculation of antigen into the immune-privileged site of the anterior chamber of the eye.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilson, S., Delovitch, T. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 3, 211–222 (2003). https://doi.org/10.1038/nri1028

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1028

This article is cited by

Search

Advanced 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