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.

Natural killer T cells: drivers or passengers in preventing human disease?

Subjects

Abstract

Natural killer T (NKT) cells are credited with regulatory roles in immunity against cancers, autoimmune diseases, allergies, and bacterial and viral infections. Studies in mice and observational research in patient groups have suggested that NKT cell-based therapies could be used to prevent or treat these diseases, yet the translation into clinical settings has been disappointing. We support the view that NKT cells have regulatory characteristics that could be exploited in clinical settings, but there are doubts about the natural roles of NKT cells in vivo and whether NKT cell defects are fundamental drivers of disease in humans. In this Opinion article, we discuss the uncertainties and opportunities regarding NKT cells in humans, and the potential for NKT cells to be manipulated to prevent or treat disease.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

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

    CAS  PubMed  Article  Google Scholar 

  2. Salio, M., Silk, J. D., Yvonne Jones, E. & Cerundolo, V. Biology of CD1- and MR1-restricted T cells. Annu. Rev. Immunol. 32, 323–366 (2014).

    CAS  PubMed  Article  Google Scholar 

  3. Berzins, S. P., Smyth, M. J. & Baxter, A. G. Presumed guilty: natural killer T cell defects and human disease. Nature Rev. Immunol. 11, 131–142 (2011).

    CAS  Article  Google Scholar 

  4. Exley, M. A. & Nakayama, T. NKT-cell-based immunotherapies in clinical trials. Clin. Immunol. 140, 117–118 (2011).

    CAS  PubMed  Article  Google Scholar 

  5. 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  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  7. Rossjohn, J., Pellicci, D. G., Patel, O., Gapin, L. & Godfrey, D. I. Recognition of CD1d-restricted antigens by natural killer T cells. Nature Rev. Immunol. 12, 845–857 (2012).

    CAS  Article  Google Scholar 

  8. Godfrey, D. I. & Rossjohn, J. New ways to turn on NKT cells. J. Exp. Med. 208, 1121–1125 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Kinjo, Y. et al. Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nature Immunol. 12, 966–974 (2011).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  12. Brennan, P. J., Brigl, M. & Brenner, M. B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nature Rev. Immunol. 13, 101–117 (2013).

    CAS  Article  Google Scholar 

  13. Gapin, L., Godfrey, D. I. & Rossjohn, J. Natural killer T cell obsession with self-antigens. Curr. Opin. Immunol. 25, 168–173 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Holzapfel, K. L., Tyznik, A. J., Kronenberg, M. & Hogquist, K. A. Antigen-dependent versus -independent activation of invariant NKT cells during infection. J. Immunol. 192, 5490–5498 (2014).

    CAS  PubMed  Article  Google Scholar 

  15. Crowe, N. Y. et al. Differential antitumor immunity mediated by NKT cell subsets in vivo. J. Exp. Med. 202, 1279–1288 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 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  Article  Google Scholar 

  17. 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  PubMed  Article  Google Scholar 

  18. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Berzofsky, J. A. & Terabe, M. NKT cells in tumor immunity: opposing subsets define a new immunoregulatory axis. J. Immunol. 180, 3627–3635 (2008).

    CAS  Article  PubMed  Google Scholar 

  20. Vivier, E., Ugolini, S., Blaise, D., Chabannon, C. & Brossay, L. Targeting natural killer cells and natural killer T cells in cancer. Nature Rev. Immunology 12, 239–252 (2012).

    CAS  Article  Google Scholar 

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

    CAS  Article  PubMed Central  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  23. 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).

    CAS  PubMed  Article  Google Scholar 

  24. Lehuen, A., Diana, J., Zaccone, P. & Cooke, A. Immune cell crosstalk in type 1 diabetes. Nature Rev. Immunol. 10, 501–513 (2010).

    CAS  Article  Google Scholar 

  25. Kim, H. Y., DeKruyff, R. H. & Umetsu, D. T. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nature Immunol. 11, 577–584 (2010).

    CAS  Article  Google Scholar 

  26. Holtzman, M. J. Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens. J. Clin. Invest. 122, 2741–2748 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 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 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 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).

    CAS  PubMed  Article  Google Scholar 

  33. 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).

    PubMed  Article  Google Scholar 

  34. 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).

    CAS  PubMed  Article  Google Scholar 

  35. 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).

    PubMed  Article  Google Scholar 

  36. de Lalla, C. et al. Invariant NKT cell reconstitution in pediatric leukemia patients given HLA-haploidentical stem cell transplantation defines distinct CD4+ and CD4 subset dynamics and correlates with remission state. J. Immunol. 186, 4490–4499 (2011).

    CAS  PubMed  Article  Google Scholar 

  37. Rubio, M. T. et al. Early posttransplantation donor-derived invariant natural killer T-cell recovery predicts the occurrence of acute graft-versus-host disease and overall survival. Blood 120, 2144–2154 (2012).

    CAS  PubMed  Article  Google Scholar 

  38. Yamasaki, K. et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin. Immunol. 138, 255–265 (2011).

    CAS  PubMed  Article  Google Scholar 

  39. Fujii, S. I. et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front. Immunol. 4, 409 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. Fletcher, J. M. et al. Congenic analysis of the NKT cell control gene Nkt2 implicates the peroxisomal protein Pxmp4. J. Immunol. 181, 3400–3412 (2008).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  42. Simoni, Y., Diana, J., Ghazarian, L., Beaudoin, L. & Lehuen, A. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality? Clin. Exp. Immunol. 171, 8–19 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  44. Matangkasombut, P. et al. Natural killer T cells in the lungs of patients with asthma. J. Allergy Clin. Immunol. 123, 1181–1185 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  46. Reynolds, C. et al. Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma. J. Allergy Clin. Immunol. 124, 860–862 (2009).

    CAS  Article  PubMed  Google Scholar 

  47. 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).

    CAS  PubMed  Article  Google Scholar 

  48. 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).

    CAS  PubMed  Article  Google Scholar 

  49. 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).

    CAS  Article  PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Metelitsa, L. S. Anti-tumor potential of type-I NKT cells against CD1d-positive and CD1d-negative tumors in humans. Clin. Immunol. 140, 119–129 (2011).

    CAS  PubMed  Article  Google Scholar 

  52. 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 

  53. Uldrich, A. P. et al. NKT cell stimulation with glycolipid antigen in vivo: costimulation-dependent expansion, Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge. J. Immunol. 175, 3092–3101 (2005).

    CAS  PubMed  Article  Google Scholar 

  54. Parekh, V. V., Lalani, S. & Van Kaer, L. The in vivo response of invariant natural killer T cells to glycolipid antigens. Int. Rev. Immunol. 26, 31–48 (2007).

    CAS  PubMed  Article  Google Scholar 

  55. Fujii, S., Shimizu, K., Smith, C., Bonifaz, L. & Steinman, R. M. Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J. Exp. Med. 198, 267–279 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Cerundolo, V., Barral, P. & Batista, F. D. Synthetic iNKT cell-agonists as vaccine adjuvants—finding the balance. Curr. Opin. Immunol. 22, 417–424 (2010).

    CAS  PubMed  Article  Google Scholar 

  57. Motohashi, S., Okamoto, Y., Yoshino, I. & Nakayama, T. Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. Clin. Immunol. 140, 167–176 (2011).

    CAS  PubMed  Article  Google Scholar 

  58. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Yu, K. O. et al. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of α-galactosylceramides. Proc. Natl Acad. Sci. USA 102, 3383–3388 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Davis, M. M. A prescription for human immunology. Immunity 29, 835–838 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Le Bourhis, L. et al. Mucosal-associated invariant T cells: unconventional development and function. Trends Immunol. 32, 212–218 (2011).

    CAS  PubMed  Article  Google Scholar 

  62. Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).

    CAS  Article  PubMed  Google Scholar 

  63. Bedel, R. et al. Lower TCR repertoire diversity in Traj18-deficient mice. Nature Immunol. 13, 705–706 (2012).

    CAS  Article  Google Scholar 

  64. 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).

    Article  PubMed  Google Scholar 

  65. 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  Article  Google Scholar 

  66. Wallace, K. L. et al. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines. Blood 114, 667–676 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 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  Article  Google Scholar 

  68. Michel, M. L. et al. Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia. J. Exp. Med. 204, 995–1001 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    CAS  Article  PubMed  Google Scholar 

  71. 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  Article  Google Scholar 

  72. Kammertoens, T., Qin, Z., Briesemeister, D., Bendelac, A. & Blankenstein, T. B-cells and IL-4 promote methylcholanthrene-induced carcinogenesis but there is no evidence for a role of T/NKT-cells and their effector molecules (Fas-ligand, TNF-α, perforin). Int. J. Cancer 131, 1499–1508 (2012).

    CAS  PubMed  Article  Google Scholar 

  73. Nowak, M. et al. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with α-galactosylceramide. PLoS ONE 5, e11311 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Kawano, T. et al. Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells. Proc. Natl Acad. Sci. USA 95, 5690–5693 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. Mattarollo, S. R., Kenna, T., Nieda, M. & Nicol, A. J. Chemotherapy pretreatment sensitizes solid tumor-derived cell lines to Vα24+ NKT cell-mediated cytotoxicity. Int. J. Cancer 119, 1630–1637 (2006).

    CAS  PubMed  Article  Google Scholar 

  76. Shimizu, K., Kurosawa, Y., Taniguchi, M., Steinman, R. M. & Fujii, S. Cross-presentation of glycolipid from tumor cells loaded with α-galactosylceramide leads to potent and long-lived T cell mediated immunity via dendritic cells. J. Exp. Med. 204, 2641–2653 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Song, L. et al. Vα24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J. Clin. Invest. 119, 1524–1536 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Motohashi, S. et al. A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin. Cancer Res. 12, 6079–6086 (2006).

    CAS  Article  PubMed  Google Scholar 

  79. 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).

    CAS  PubMed  Article  Google Scholar 

  80. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 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).

    CAS  PubMed  Article  Google Scholar 

  82. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  84. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 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).

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  88. Chan, A. C. et al. Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients. Leukemia 24, 592–600 (2010).

    CAS  PubMed  Article  Google Scholar 

  89. Chan, A. C. et al. Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy. Clin. Exp. Immunol. 175, 49–58 (2014).

    CAS  PubMed  Article  Google Scholar 

  90. Schneiders, F. L. et al. Clinical experience with alpha-galactosylceramide (KRN7000) in patients with advanced cancer and chronic hepatitis B/C infection. Clin. Immunol. 140, 130–141 (2011).

    CAS  PubMed  Article  Google Scholar 

  91. Hermans, I. F. et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J. Immunol. 171, 5140–5147 (2003).

    CAS  Article  PubMed  Google Scholar 

  92. Burdin, N., Brossay, L. & Kronenberg, M. Immunization with α-galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur. J. Immunol. 29, 2014–2025 (1999).

    CAS  PubMed  Article  Google Scholar 

  93. van der Vliet, H. J. et al. Polarization of Vα24+ Vβ11+ natural killer T cells of healthy volunteers and cancer patients using α-galactosylceramide-loaded and environmentally instructed dendritic cells. Cancer Res. 63, 4101–4106 (2003).

    CAS  PubMed  Google Scholar 

  94. Song, W. et al. Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy. Clin. Cancer Res. 14, 6955–6962 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Zhu, D., Corral, L. G., Fleming, Y. W. & Stein, B. Immunomodulatory drugs Revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol. Immunother. 57, 1849–1859 (2008).

    CAS  PubMed  Article  Google Scholar 

  96. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Motohashi, S. et al. Preserved IFN-α production of circulating Vα24 NKT cells in primary lung cancer patients. Int. J. Cancer 102, 159–165 (2002).

    CAS  PubMed  Article  Google Scholar 

  98. Baxter, A. G., Kinder, S. J., Hammond, K. J. L., Scollay, R. & Godfrey, D. I. Association between α-β-TCR+CD4CD8 T-cell deficiency and IDDM in NOD/Lt mice. Diabetes 46, 572–582 (1997).

    CAS  PubMed  Article  Google Scholar 

  99. Godfrey, D. I., Kinder, S. J., Silvera, P. & Baxter, A. G. Flow cytometric study of T cell development in NOD mice reveals a deficiency in αβTCR+CDRCD8 thymocytes. J. Autoimmun 10, 279–285 (1997).

    CAS  PubMed  Article  Google Scholar 

  100. Poulton, L. D. & Baxter, A. G. Clinical application of NKT cell assays to the prediction of type 1 diabetes. Diabetes Metab. Res. Rev. 17, 429–435 (2001).

    CAS  PubMed  Article  Google Scholar 

  101. Hammond, K. J. L. et al. α/β-T cell receptor (TCR)+CD4CD8 (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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Beaudoin, L., Laloux, V., Novak, J., Lucas, B. & Lehuen, A. 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).

    CAS  PubMed  Article  Google Scholar 

  103. 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  Article  Google Scholar 

  104. 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).

    CAS  PubMed  Article  Google Scholar 

  105. Novak, J. et al. Prevention of type 1 diabetes by invariant NKT cells is independent of peripheral CD1d expression. J. Immunol. 178, 1332–1340 (2007).

    CAS  PubMed  Article  Google Scholar 

  106. Forestier, C. et al. Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator. J. Immunol. 178, 1415–1425 (2007).

    CAS  PubMed  Article  Google Scholar 

  107. Ly, D., Mi, Q. S., Hussain, S. & Delovitch, T. L. Protection from type 1 diabetes by invariant NK T cells requires the activity of CD4+CD25+ regulatory T cells. J. Immunol. 177, 3695–3704 (2006).

    CAS  PubMed  Article  Google Scholar 

  108. Beaudoin, L. et al. Plasmacytoid dendritic cells license regulatory T cells, upon iNKT-cell stimulation, to prevent autoimmune diabetes. Eur. J. Immunol. 44, 1454–1466 (2014).

    CAS  PubMed  Article  Google Scholar 

  109. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 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).

    CAS  PubMed  Article  Google Scholar 

  111. Oikawa, Y. et al. High frequency of vα24+ vβ11+ T-cells observed in type 1 diabetes. Diabetes Care 25, 1818–1823 (2002).

    PubMed  Article  Google Scholar 

  112. 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).

    CAS  PubMed  Article  Google Scholar 

  113. 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).

    CAS  PubMed  Article  Google Scholar 

  114. 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).

    CAS  PubMed  Article  Google Scholar 

  115. Lisbonne, M. et al. Cutting edge: invariant Vα14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J. Immunol. 171, 1637–1641 (2003).

    CAS  PubMed  Article  Google Scholar 

  116. Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Herrick, C. A. & Bottomly, K. To respond or not to respond: T cells in allergic asthma. Nature Rev. Immunol. 3, 405–412 (2003).

    CAS  Article  Google Scholar 

  118. Umetsu, D. T., Meyer, E. H. & DeKruyff, R. H. Natural killer T cells regulate the development of asthma. Int. Rev. Immunol. 26, 121–140 (2007).

    PubMed  Article  Google Scholar 

  119. Pichavant, M. et al. Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J. Exp. Med. 205, 385–393 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Simoni, Y. et al. NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes. Eur. J. Immunol. 41, 3574–3585 (2011).

    CAS  PubMed  Article  Google Scholar 

  121. Robinson, D. S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).

    CAS  Article  PubMed  Google Scholar 

  122. Meyer, E. H. et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc. Natl Acad. Sci. USA 103, 2782–2787 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Akbari, O. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nature Med. 9, 582–588 (2003).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank Prof. A. Baxter for helpful advice during the planning and preparation of this article.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Stuart P. Berzins or David S. Ritchie.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Berzins, S., Ritchie, D. Natural killer T cells: drivers or passengers in preventing human disease?. Nat Rev Immunol 14, 640–646 (2014). https://doi.org/10.1038/nri3725

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3725

Further reading

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