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:

Presumed guilty: natural killer T cell defects and human disease

Subjects

Key Points

  • Type 1 natural killer T (NKT) cells are potent cytokine producers that express a CD1d-restricted, semi-invariant T cell receptor that is specific for glycolipid antigens.

  • Type 1 NKT cells are thought to be important for maintaining immune self-tolerance and for promoting immunity to tumours, bacteria and viruses. The incidence of some autoimmune diseases, cancers and infections is increased in mice with NKT cell defects, and protection from these conditions can be conferred by NKT cell stimulation or replenishment.

  • NKT cell defects have also been identified in humans with similar types of disease, but these studies have mostly been association studies and many have lacked stringent methods for the identification of NKT cells and have carried out only a limited analysis of cell surface antigen expression and cytokine production by the NKT cell subsets. As a result, there is uncertainty about the nature and significance of NKT cell defects in the human type 1 NKT cell pool and the potential for NKT cells to become a clinically useful factor in patient care.

  • To achieve a consensus view about the significance of NKT cells in human disease, the analysis of type 1 NKT cells from patients with conditions associated with NKT cell defects should include detailed characterization of cell surface antigen expression and cytokine production by the NKT cell subsets. The small volume of blood available for clinical studies can limit the types of assay used, but improved methods and an increased understanding of human NKT cell subsets, including the implications of particular patterns of cell surface antigen expression, should allow for a more detailed evaluation of the NKT cell pool of patients.

  • Longitudinal studies of NKT cells from patients with chronic diseases, or from individuals at increased risk of acute disease, will be important to determine whether NKT cell defects predispose to these conditions or whether they develop as a secondary effect of the disease.

  • Confirming and characterizing NKT cell defects in different patient groups could enable the development of NKT cell-based therapies to treat or prevent these conditions.

Abstract

Natural killer T (NKT) cells are important regulatory lymphocytes that have been shown in mouse studies, to have a crucial role in promoting immunity to tumours, bacteria and viruses, and in suppressing cell-mediated autoimmunity. Many clinical studies have indicated that NKT cell deficiencies and functional defects might also contribute to similar human diseases, although there is no real consensus about the nature of the NKT cell defects or whether NKT cells could be important for the diagnosis and/or treatment of these conditions. In this Review, we describe the approaches that have been used to analyse the NKT cell populations of various patient groups, suggest new strategies to determine how (or indeed, if) NKT cell defects contribute to human disease, and discuss the prospects for using NKT cells for therapeutic benefit.

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: NKT cell defects and disease.
Figure 2: Potential clinical uses for NKT cells.

Similar content being viewed by others

References

  1. Godfrey, D. I., MacDonald, H. R., Kronenberg, M., Smyth, M. J. & Van Kaer, L. NKT cells: what's in a name? Nature Rev. Immunol. 4, 231–237 (2004).

    CAS  Google Scholar 

  2. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Matsuda, J. L., Mallevaey, T., Scott-Browne, J. & Gapin, L. CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system. Curr. Opin. Immunol. 20, 358–368 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. De Santo, C. et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J. Clin. Invest. 118, 4036–4048 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Santo, C. et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nature Immunol. 11, 1039–1046 (2010).

    Article  CAS  Google Scholar 

  7. Crowe, N. Y. et al. Differential antitumor immunity mediated by NKT cell subsets in vivo. J. Exp. Med. 202, 1279–1288 (2005). This was the first in vivo study to show differential antitumour activity by different NKT cell subsets in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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). References 8–10 were pivotal in identifying heterogeneity within the human NKT cell compartment, including the functional characterization of CD4+ and CD4 subsets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Montoya, C. J. et al. Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. Immunology 122, 1–14 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Godfrey, D. I., Stankovic, S. & Baxter, A. G. Raising the NKT cell family. Nature Immunol. 11, 197–206 (2010).

    Article  CAS  Google Scholar 

  13. Lee, P. T. et al. Testing the NKT cell hypothesis of human IDDM pathogenesis. J. Clin. Invest. 110, 793–800 (2002). References 13 and 42 illustrate the lack of consensus regarding NKT cell defects in patients with type 1 diabetes. Reference 13 is a comprehensive study showing normal NKT cell frequency and function in patients with type 1 diabetes. It contradicts the earlier report in reference 42, which identifies an NKT cell defect in patients with type 1 diabetes. Both sides of the debate have been supported by subsequent independent studies and the issue remains unresolved.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chan, A. C. et al. Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients. Leukemia 24, 592–600 (2010). References 14 and 70–72 illustrate the lack of consensus regarding NKT cell defects in patients with haematological cancer. Reference 14 found no defects or changes in NKT cells in patients with myelodysplastic syndromes treated with lenalidomide, which is in contrast to the collective findings from the three earlier studies (references 70–72), each of which used different methods to analyse the NKT cells.

    Article  CAS  PubMed  Google Scholar 

  15. Chan, A. C. et al. Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family. Clin. Exp. Immunol. 156, 238–245 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Baev, D. V. et al. Distinct homeostatic requirements of CD4+ and CD4 subsets of Vα24-invariant natural killer T cells in humans. Blood 104, 4150–4156 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Berzins, S. P., Cochrane, A. D., Pellicci, D. G., Smyth, M. J. & Godfrey, D. I. Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples. Eur. J. Immunol. 35, 1399–1407 (2005). References 16 and 17 were the first to characterize NKT cell development in the human thymus. They illustrate important differences between thymus and blood NKT cells and indirectly show that some important stages of NKT cell differentiation occur in the periphery.

    Article  CAS  PubMed  Google Scholar 

  18. Kenna, T. et al. NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells. J. Immunol. 171, 1775–1779 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Lynch, L. et al. Invariant NKT cells and CD1d+ cells amass in human omentum and are depleted in patients with cancer and obesity. Eur. J. Immunol. 39, 1893–1901 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Exley, M. A. et al. Cutting edge: A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J. Immunol. 167, 5531–5534 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Gapin, L. Where do MAIT cells fit in the family of unconventional T cells? PLoS Biol. 7, e70 (2009).

    Article  PubMed  CAS  Google Scholar 

  22. Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Wu, L. & Van Kaer, L. Natural killer T cells and autoimmune disease. Curr. Mol. Med. 9, 4–14 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Swann, J. B., Coquet, J. M., Smyth, M. J. & Godfrey, D. I. CD1-restricted T cells and tumor immunity. Curr. Top. Microbiol. Immunol. 314, 293–323 (2007).

    CAS  PubMed  Google Scholar 

  25. Balato, A., Unutmaz, D. & Gaspari, A. A. Natural killer T cells: an unconventional T-cell subset with diverse effector and regulatory functions. J. Invest. Dermatol. 129, 1628–1642 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Berzins, S. P., Smyth, M. J. & Godfrey, D. I. Working with NKT cells — pitfalls and practicalities. Curr. Opin. Immunol. 17, 448–454 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Gadola, S. D., Dulphy, N., Salio, M. & Cerundolo, V. Vα24–JαQ-independent, CD1d-restricted recognition of α-galactosylceramide by human CD4+ and CD8αβ+ T lymphocytes. J. Immunol. 168, 5514–5520 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Kim, C. H., Butcher, E. C. & Johnston, B. Distinct subsets of human Vα24-invariant NKT cells: cytokine responses and chemokine receptor expression. Trends Immunol. 23, 516–519 (2002).

    CAS  Google Scholar 

  29. Montoya, C. J. et al. Invariant NKT cells from HIV-1 or Mycobacterium tuberculosis-infected patients express an activated phenotype. Clin. Immunol. 127, 1–6 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Araki, M. et al. TH2 bias of CD4+ NKT cells derived from multiple sclerosis in remission. Int. Immunol. 15, 279–288 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Gausling, R., Trollmo, C. & Hafler, D. A. Decreases in interleukin-4 secretion by invariant CD4CD8Vα24JαQ T cells in peripheral blood of patients with relapsing–remitting multiple sclerosis. Clin. Immunol. 98, 11–17 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Dhodapkar, M. V. et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J. Exp. Med. 197, 1667–1676 (2003). This study shows that clinical progression in patients with monoclonal gammopathies is associated with an acquired, but potentially reversible, defect in NKT cell function. The study supports the possibility that NKT cells have a role in controlling the malignant growth of multiple myeloma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Terabe, M. & Berzofsky, J. A. The role of NKT cells in tumor immunity. Adv. Cancer Res. 101, 277–348 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu, L., Gabriel, C. L., Parekh, V. V. & Van Kaer, L. Invariant natural killer T cells: innate-like T cells with potent immunomodulatory activities. Tissue Antigens 73, 535–545 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. van der Vliet, H. J. 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). This report details NKT cell defects in a wide range of human conditions.

    Article  CAS  PubMed  Google Scholar 

  37. Fletcher, M. T. & Baxter, A. G. Clinical application of NKT cell biology in type I (autoimmune) diabetes mellitus. Immunol. Cell Biol. 87, 315–323 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Novak, J., Griseri, T., Beaudoin, L. & Lehuen, A. Regulation of type 1 diabetes by NKT cells. Int. Rev. Immunol. 26, 49–72 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, B., Geng, Y. B. & Wang, C. R. CD1-restricted NK T cells protect nonobese diabetic mice from developing diabetes. J. Exp. Med. 194, 313–320 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Wilson, S. B. et al. Extreme TH1 bias of invariant Vα24JαQ T cells in type 1 diabetes. Nature 391, 177–181 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Kent, S. C. et al. Loss of IL-4 secretion from human type 1a diabetic pancreatic draining lymph node NKT cells. J. Immunol. 175, 4458–4464 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Kis, J. et al. Reduced CD4+ subset and TH1 bias of the human iNKT cells in type 1 diabetes mellitus. J. Leukoc. Biol. 81, 654–662 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Tsutsumi, Y. et al. Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with type 1 diabetes. Diabet. Med. 23, 1145–1150 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Roman-Gonzalez, A. et al. Frequency and function of circulating invariant NKT cells in autoimmune diabetes mellitus and thyroid diseases in Colombian patients. Hum. Immunol. 70, 262–268 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  48. Berzins, S. P. et al. Systemic NKT cell deficiency in NOD mice is not detected in peripheral blood: implications for human studies. Immunol. Cell Biol. 82, 247–252 (2004). This paper raises important questions about the reliance on blood for testing human NKT cells as it shows that NKT cells derived from the blood in mice do not have the same characteristics as NKT cells derived from other tissues.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Demoulins, T., Gachelin, G., Bequet, D. & Dormont, D. A biased Vα24+ T-cell repertoire leads to circulating NKT-cell defects in a multiple sclerosis patient at the onset of his disease. Immunol. Lett. 90, 223–228 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. Gigli, G., Caielli, S., Cutuli, D. & Falcone, M. Innate immunity modulates autoimmunity: type 1 interferon-β treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation. Immunology 122, 409–417 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000). This study describes a natural role for NKT cells in tumour immune surveillance in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Swann, J. B. et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113, 6382–6385 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Molling, J. W. et al. Peripheral blood IFN-γ-secreting Vα24+Vβ11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int. J. Cancer 116, 87–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Gulubova, M., Manolova, I., Kyurkchiev, D., Julianov, A. & Altunkova, I. Decrease in intrahepatic CD56+ lymphocytes in gastric and colorectal cancer patients with liver metastases. APMIS 117, 870–879 (2009).

    Article  PubMed  Google Scholar 

  57. Konishi, J. et al. The characteristics of human NKT cells in lung cancer — CD1d independent cytotoxicity against lung cancer cells by NKT cells and decreased human NKT cell response in lung cancer patients. Hum. Immunol. 65, 1377–1388 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Song, L. et al. Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. J. Clin. Invest. 117, 2702–2712 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Molling, J. W. et al. Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J. Clin. Oncol. 25, 862–868 (2007).

    Article  PubMed  Google Scholar 

  60. Kobayashi, K. et al. The effect of radiotherapy on NKT cells in patients with advanced head and neck cancer. Cancer Immunol. Immunother. 59, 1503–1509 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Tachibana, T. et al. Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin. Cancer Res. 11, 7322–7327 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Bricard, G. et al. Enrichment of human CD4+ Vα24/Vβ11 invariant NKT cells in intrahepatic malignant tumors. J. Immunol. 182, 5140–5151 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. van der Vliet, H. J. et al. Circulating myeloid dendritic cells of advanced cancer patients result in reduced activation and a biased cytokine profile in invariant NKT cells. J. Immunol. 180, 7287–7293 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Tahir, S. M. et al. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J. Immunol. 167, 4046–4050 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Metelitsa, L. S. et al. Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells. J. Immunol. 167, 3114–3122 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Neparidze, N. & Dhodapkar, M. V. Harnessing CD1d-restricted T cells toward antitumor immunity in humans. Ann. NY Acad. Sci. 1174, 61–67 (2009). This review provides an interesting account of how NKT cells might become useful for the treatment of cancer.

    Article  CAS  PubMed  Google Scholar 

  67. Shimizu, K. et al. Evaluation of the function of human invariant NKT cells from cancer patients using α-galactosylceramide-loaded murine dendritic cells. J. Immunol. 177, 3484–3492 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Dhodapkar, M. V. Harnessing human CD1d restricted T cells for tumor immunity: progress and challenges. Front. Biosci. 14, 796–807 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  69. Chang, D. H. et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 108, 618–621 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zeng, W. et al. Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br. J. Haematol. 119, 803–809 (2002).

    Article  PubMed  Google Scholar 

  71. Fujii, S. et al. Severe and selective deficiency of interferon-γ-producing invariant natural killer T cells in patients with myelodysplastic syndromes. Br. J. Haematol. 122, 617–622 (2003).

    Article  PubMed  Google Scholar 

  72. Yoneda, K. et al. The peripheral blood Vα24+ NKT cell numbers decrease in patients with haematopoietic malignancy. Leuk. Res. 29, 147–152 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Shah, S. R. & Tran, T. M. Lenalidomide in myelodysplastic syndrome and multiple myeloma. Drugs 67, 1869–1881 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Spanoudakis, E. et al. Regulation of multiple myeloma survival and progression by CD1d. Blood 113, 2498–2507 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Chang, D. H. et al. Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer. Blood 112, 1308–1316 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gorgun, G. et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 116, 3227–3237 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nieuwenhuis, E. E. S. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nature Med. 8, 588–593 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Skold, M. & Behar, S. M. Role of CD1d-restricted NKT cells in microbial immunity. Infect. Immun. 71, 5447–5455 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Vincent, M. S., Gumperz, J. E. & Brenner, M. B. Understanding the function of CD1-restricted T cells. Nature Immunol. 4, 517–523 (2003).

    Article  CAS  Google Scholar 

  80. Kinjo, Y. et al. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nature Immunol. 7, 978–986 (2006).

    Article  CAS  Google Scholar 

  81. Mattner, J. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434, 525–529 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Kinjo, Y. et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005). References 80–82 describe the identification of exogenous glycolipids that are recognized by human NKT cells.

    Article  CAS  PubMed  Google Scholar 

  83. Sutherland, J. S. et al. High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease in a TB-endemic setting. Tuberculosis 89, 398–404 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Im, J. S. et al. Alteration of the relative levels of iNKT cell subsets is associated with chronic mycobacterial infections. Clin. Immunol. 127, 214–224 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Veenstra, H. et al. Changes in leucocyte and lymphocyte subsets during tuberculosis treatment; prominence of CD3dimCD56+ natural killer T cells in fast treatment responders. Clin. Exp. Immunol. 145, 252–260 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Thomas, S. Y., Chyung, Y. H. & Luster, A. D. Natural killer T cells are not the predominant T cell in asthma and likely modulate, not cause, asthma. J. Allergy Clin. Immunol. 125, 980–984 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Umetsu, D. T. & Dekruyff, R. H. Natural killer T cells are important in the pathogenesis of asthma: the many pathways to asthma. J. Allergy Clin. Immunol. 125, 975–979 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Braun, N. A., Covarrubias, R. & Major, A. S. Natural killer T cells and atherosclerosis: form and function meet pathogenesis. J. Innate Immun. 2, 316–324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kyriakakis, E. et al. Invariant natural killer T cells: linking inflammation and neovascularization in human atherosclerosis. Eur. J. Immunol. 40, 3268–3279 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  91. Nieda, M. et al. Therapeutic activation of Vα24+Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103, 383–389 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Ishikawa, A. et al. A phase I study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin. Cancer Res. 11, 1910–1917 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Chang, D. H. et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 201, 1503–1517 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kunii, N. et al. Combination therapy of in vitro-expanded natural killer T cells and α-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma. Cancer Sci. 100, 1092–1098 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Cerundolo, V., Barral, P. & Batista, F. D. Synthetic iNKT cell-agonists as vaccine adjuvants — finding the balance. Curr. Opin. Immunol. 22, 417–424 (2010). This review describes the prospects for using NKT cells to improve vaccine efficacy.

    Article  CAS  PubMed  Google Scholar 

  96. Akbari, O. et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117–1129 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Thomas, S. Y., Lilly, C. M. & Luster, A. D. Invariant natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 2613–2616 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Vijayanand, P. et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 1410–1422 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Brooks, C. R., Weinkove, R., Hermans, I. F., van Dalen, C. J. & Douwes, J. Invariant natural killer T cells and asthma: immunologic reality or methodologic artifact? J. Allergy Clin. Immunol. 126, 882–885 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Esteban, L. M. et al. Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J. Immunol. 171, 2873–2878 (2003). This study illustrates the potential for genetic approaches to identify the genes responsible for NKT cell defects.

    Article  CAS  PubMed  Google Scholar 

  101. Borowski, C. & Bendelac, A. Signaling for NKT cell development: the SAP–FynT connection. J. Exp. Med. 201, 833–836 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Godfrey, D. I. & Berzins, S. P. Control points in NKT-cell development. Nature Rev. Immunol. 7, 505–518 (2007).

    Article  CAS  Google Scholar 

  104. Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Brigl, M., Bry, L., Kent, S. C., Gumperz, J. E. & Brenner, M. B. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nature Immunol. 4, 1230–1237 (2003).

    Article  CAS  Google Scholar 

  106. Fox, L. M. et al. Recognition of lyso-phospholipids by human natural killer T lymphocytes. PLoS Biol. 7, e1000228 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Hegde, S., Fox, L., Wang, X. & Gumperz, J. E. Autoreactive natural killer T cells: promoting immune protection and immune tolerance through varied interactions with myeloid antigen-presenting cells. Immunology 130, 471–483 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Barral, P. et al. CD169+ macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nature Immunol. 11, 303–312 (2010). This paper provides an insight into how and where NKT cells become activated during an in vivo immune response.

    Article  CAS  Google Scholar 

  109. Cerundolo, V. & Salio, M. Harnessing NKT cells for therapeutic applications. Curr. Top. Microbiol. Immunol. 314, 325–340 (2007).

    CAS  PubMed  Google Scholar 

  110. Coquet, J. M. et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4NK1.1 NKT cell population. Proc. Natl Acad. Sci. USA 105, 11287–11292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

S.P.B. is supported by an Australian National Health and Medical Research Council (NHMRC) R. D. Wright Fellowship. M.J.S. is supported by an Australian NHMRC Australia Fellowship and Program Grant. A.G.B. is supported by an Australian NHMRC Senior Research Fellowship. We thank D. Godfrey and A. Chan for helpful advice during the planning and preparation of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stuart P. Berzins.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berzins, S., Smyth, M. & Baxter, A. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 11, 131–142 (2011). https://doi.org/10.1038/nri2904

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2904

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