International Journal of Hematology

, Volume 90, Issue 2, pp 137–142

Human invariant natural killer T cells: implications for immunotherapy

Review Article

Abstract

Human invariant natural killer T cells are a unique lymphocyte population that have an invariant T-cell receptor and recognize glycolipids instead of peptides in the restriction of CD1d molecules. These natural killer T cells play important roles in anti-tumor immunity, transplantation immunity, allergy, autoimmunity and microbial immunity. Since human natural killer T cells show high-level biological activity such as cytokine production, an anti-tumor effect and regulatory T-cell control, they may be a useful tool in immune-cell therapy. In this review, we summarize the immune responses mediated by human natural killer T cells, especially in tumor and transplantation immunity, and discuss their potential in clinical applications.

Keywords

NKT Immunotherapy Tumor immunity Transplantation immunity 

References

  1. 1.
    Lanier LL, Chang C, Phillips JH. Human NKR-P1A: a disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol. 1994;153:2417–28.PubMedGoogle Scholar
  2. 2.
    Werwitzke S, Tiede A, Drescher BE, Schmidt RE, Witte T. CD8β/CD28 expression defines functionally distinct populations of peripheral blood T lymphocytes. Clin Exp Immunol. 2003;133:334–43.PubMedCrossRefGoogle Scholar
  3. 3.
    Gumperz JE, Miyake S, Yamamura T, Brenner MB. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med. 2002;195:625–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Ishihara S, Nieda M, Kitayama J, et al. CD8(+) NKR-P1A(+) T cells preferentially accumulate in human liver. Eur J Immunol. 1999;29:2406–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest. 2004;114:1379–88.PubMedGoogle Scholar
  6. 6.
    Smyth MJ, Thia KY, Street SE, et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. 2000;191:661–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Azuma T, Takahashi T, Kunisato A, Kitamura T, Hirai H. Human CD4+ CD25+ regulatory T cells suppress NKT cell functions. Cancer Res. 2003;63:4516–20.PubMedGoogle Scholar
  8. 8.
    Liu R, La Cava A, Bai XF, et al. Cooperation of invariant NKT cells and CD4+CD25+ T regulatory cells in the prevention of autoimmune myasthenia. J Immunol. 2005;175:7898–904.PubMedGoogle Scholar
  9. 9.
    Rogers PR, Matsumoto A, Naidenko O, Kronenberg M, Mikayama T, Kato S. Expansion of human Vα24+ NKT cells by repeated stimulation with KRN7000. J Immunol Methods. 2004;285:197–214.PubMedCrossRefGoogle Scholar
  10. 10.
    Fowlkes BJ, Kruisbeek AM, Ton-That H, et al. A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vβ gene family. Nature. 1987;329:251–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Budd RC, Miescher GC, Howe RC, Lees RK, Bron C, MacDonald HR. Developmentally regulated expression of T cell receptor beta chain variable domains in immature thymocytes. J Exp Med. 1987;166:577–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Lantz O, Bendelac A. An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4–8- T cells in mice and humans. J Exp Med. 1994;180:1097–106.PubMedCrossRefGoogle Scholar
  13. 13.
    Hammond KJ, Pellicci DG, Poulton LD, et al. CD1d-restricted NKT cells: an interstrain comparison. J Immunol. 2001;167:1164–73.PubMedGoogle Scholar
  14. 14.
    Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol. 2004;4:231–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Exley M, Garcia J, Balk SP, Porcelli S. Requirements for CD1d recognition by human invariant Vα24+ CD4CD8 T cells. J Exp Med. 1997;186:109–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Nieda M, Nicol A, Koezuka Y, et al. Activation of human Vα24NKT cells by α-glycosylceramide in a CD1d-restricted and Vα24TCR-mediated manner. Hum Immunol. 1999;60:10–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Takahashi T, Nieda M, Koezuka Y, et al. Analysis of human Vα24+ CD4+ NKT cells activated by α-glycosylceramide-pulsed monocyte-derived dendritic cells. J Immunol. 2000;164:4458–64.PubMedGoogle Scholar
  18. 18.
    Dellabona P, Casorati G, Friedli B, et al. In vivo persistence of expanded clones specific for bacterial antigens within the human T cell receptor α/β CD4–8- subset. J Exp Med. 1993;177:1763–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Porcelli S, Yockey CE, Brenner MB, Balk SP. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD48 α/β T cells demonstrates preferential use of several Vβ genes and an invariant TCR α chain. J Exp Med. 1993;178:1–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Dellabona P, Padovan E, Casorati G, Brockhaus M, Lanzavecchia A. An invariant V α24-JαQ/Vβ11 T cell receptor is expressed in all individuals by clonally expanded CD4–8- T cells. J Exp Med. 1994;180:1171–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Davodeau F, Peyrat MA, Necker A, et al. Close phenotypic and functional similarities between human and murine αβ T cells expressing invariant TCR α-chains. J Immunol. 1997;158:5603–11.PubMedGoogle Scholar
  22. 22.
    Exley MA, Tahir SM, Cheng O, et al. A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J Immunol. 2001;167:5531–4.PubMedGoogle Scholar
  23. 23.
    Takahashi T, Nakamura K, Chiba S, Kanda Y, Tamaki K, Hirai H. Vα24+ natural killer T cells are markedly decreased in atopic dermatitis patients. Hum Immunol. 2003;64:586–92.PubMedGoogle Scholar
  24. 24.
    Takahashi T, Dejbakhsh-Jones S, Strober S. Expression of CD161 (NKR-P1A) defines subsets of human CD4 and CD8 T cells with different functional activities. J Immunol. 2006;176:211–6.PubMedGoogle Scholar
  25. 25.
    Lee PT, Benlagha K, Teyton L, Bendelac A. Distinct functional lineages of human V(alpha)24 natural killer T cells. J Exp Med. 2002;195:637–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Takahashi T, Chiba S, Nieda M, et al. Cutting edge: analysis of human Vα 24+CD8+ NKT cells activated by α-galactosylceramide-pulsed monocyte-derived dendritic cells. J Immunol. 2002;168:3140–4.PubMedGoogle Scholar
  27. 27.
    Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol. 2007;25:297–336.PubMedCrossRefGoogle Scholar
  28. 28.
    Sakuishi K, Oki S, Araki M, Porcelli SA, Miyake S, Yamamura T. Invariant NKT cells biased for IL-5 production act as crucial regulators of inflammation. J Immunol. 2007;179:3452–62.PubMedGoogle Scholar
  29. 29.
    Chang YJ, Huang JR, Tsai YC, et al. Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids. Proc Natl Acad Sci U S A. 2007;104:10299–304.PubMedCrossRefGoogle Scholar
  30. 30.
    Kobayashi E, Motoki K, Uchida T, Fukushima H, Koezuka Y. KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res. 1995;7:529–34.PubMedGoogle Scholar
  31. 31.
    Kawano T, Cui J, Koezuka Y, et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science. 1997;278:1626–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Miyamoto K, Miyake S, Yamamura T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature. 2001;413:531–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Schmieg J, Yang G, Franck RW, Tsuji M. Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand α-galactosylceramide. J Exp Med. 2003;198:1631–41.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhou D, Mattner J, Cantu C 3rd, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science. 2004;306:1786–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Speak AO, Salio M, Neville DC, et al. Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals. Proc Natl Acad Sci U S A. 2007;104:5971–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Porubsky S, Speak AO, Luckow B, Cerundolo V, Platt FM, Grone HJ. Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency. Proc Natl Acad Sci U S A. 2007;104:5977–82.PubMedCrossRefGoogle Scholar
  37. 37.
    Mattner J, Debord KL, Ismail N, et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature. 2005;434:525–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kinjo Y, Wu D, Kim G, et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature. 2005;434:520–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Sriram V, Du W, Gervay-Hague J, Brutkiewicz RR. Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells. Eur J Immunol. 2005;35:1692–701.PubMedCrossRefGoogle Scholar
  40. 40.
    Cui J, Shin T, Kawano T, et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science. 1997;278:1623–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Kitamura H, Iwakabe K, Yahata T, 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. 1999;189:1121–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Yang YF, Tomura M, Ono S, Hamaoka T, Fujiwara H. Requirement for IFN-gamma in IL-12 production induced by collaboration between v(alpha)14(+) NKT cells and antigen-presenting cells. Int Immunol. 2000;12:1669–75.PubMedCrossRefGoogle Scholar
  43. 43.
    Tomura M, Yu WG, Ahn HJ, 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. 1999;163:93–101.PubMedGoogle Scholar
  44. 44.
    Fujii S, Shimizu K, Hemmi H, Steinman RM. Innate Vα14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol Rev. 2007;220:183–98.PubMedCrossRefGoogle Scholar
  45. 45.
    Ko HJ, Lee JM, Kim YJ, Kim YS, Lee KA, Kang CY. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine. J Immunol. 2009;182:1818–28.PubMedCrossRefGoogle Scholar
  46. 46.
    Terabe M, Matsui S, Noben-Trauth N, et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol. 2000;1:515–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE. Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol. 2000;1:521–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Metelitsa LS, Naidenko OV, Kant A, 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. 2001;167:3114–22.PubMedGoogle Scholar
  49. 49.
    Metelitsa LS, Weinberg KI, Emanuel PD, Seeger RC. Expression of CD1d by myelomonocytic leukemias provides a target for cytotoxic NKT cells. Leukemia. 2003;17:1068–77.PubMedCrossRefGoogle Scholar
  50. 50.
    Takahashi T, Haraguchi K, Chiba S, Yasukawa M, Shibata Y, Hirai H. Vα24+ natural killer T-cell responses against T-acute lymphoblastic leukaemia cells: implications for immunotherapy. Br J Haematol. 2003;122:231–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Zeng D, Lewis D, Dejbakhsh-Jones S, et al. Bone marrow NK1.1(−) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease. J Exp Med. 1999;189:1073–81.PubMedCrossRefGoogle Scholar
  52. 52.
    Lan F, Zeng D, Higuchi M, Huie P, Higgins JP, Strober S. Predominance of NK1.1+TCRαβ+ or DX5+TCRαβ+ T cells in mice conditioned with fractionated lymphoid irradiation protects against graft-versus-host disease: “natural suppressor” cells. J Immunol. 2001;167:2087–96.PubMedGoogle Scholar
  53. 53.
    Morecki S, Panigrahi S, Pizov G, et al. Effect of KRN7000 on induced graft-vs-host disease. Exp Hematol. 2004;32:630–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Hashimoto D, Asakura S, Miyake S, et al. Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells. J Immunol. 2005;174:551–6.PubMedGoogle Scholar
  55. 55.
    Haraguchi K, Takahashi T, Matsumoto A, et al. Host-residual invariant NK T cells attenuate graft-versus-host immunity. J Immunol. 2005;175:1320–8.PubMedGoogle Scholar
  56. 56.
    Haraguchi K, Takahashi T, Hiruma K, et al. Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2004;34:595–602.PubMedCrossRefGoogle Scholar
  57. 57.
    Lan F, Zeng D, Higuchi M, Higgins JP, Strober S. Host conditioning with total lymphoid irradiation and antithymocyte globulin prevents graft-versus-host disease: the role of CD1-reactive natural killer T cells. Biol Blood Marrow Transplant. 2003;9:355–63.PubMedCrossRefGoogle Scholar
  58. 58.
    Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005;353:1321–31.PubMedCrossRefGoogle Scholar
  59. 59.
    Morris ES, MacDonald KP, Rowe V, et al. NKT cell-dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs. J Clin Invest. 2005;115:3093–103.PubMedCrossRefGoogle Scholar
  60. 60.
    Pillai AB, George TI, Dutt S, Teo P, Strober S. Host NKT cells can prevent graft-versus-host disease and permit graft antitumor activity after bone marrow transplantation. J Immunol. 2007;178:6242–51.PubMedGoogle Scholar
  61. 61.
    Morris ES, MacDonald KP, Kuns RD, et al. Induction of natural killer T cell-dependent alloreactivity by administration of granulocyte colony-stimulating factor after bone marrow transplantation. Nat Med. 2009;15:436–41.PubMedCrossRefGoogle Scholar
  62. 62.
    Giaccone G, Punt CJ, Ando Y, et al. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res. 2002;8:3702–9.PubMedGoogle Scholar
  63. 63.
    Fujii S, Shimizu K, Kronenberg M, Steinman RM. Prolonged IFN-γ-producing NKT response induced with α-galactosylceramide-loaded DCs. Nat Immunol. 2002;3:867–74.PubMedCrossRefGoogle Scholar
  64. 64.
    Parekh VV, Wilson MT, Olivares-Villagomez D, et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest. 2005;115:2572–83.PubMedCrossRefGoogle Scholar
  65. 65.
    Nieda M, Okai M, Tazbirkova A, et al. Therapeutic activation of Vα24+Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood. 2004;103:383–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Ishikawa A, Motohashi S, Ishikawa E, 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. 2005;11:1910–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Motohashi S, Ishikawa A, Ishikawa E, 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. 2006;12:6079–86.PubMedCrossRefGoogle Scholar
  68. 68.
    Chang DH, Osman K, Connolly J, 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. 2005;201:1503–17.PubMedCrossRefGoogle Scholar
  69. 69.
    Uchida T, Horiguchi S, Tanaka Y, et al. Phase I study of α-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol Immunother. 2008;57:337–45.PubMedCrossRefGoogle Scholar
  70. 70.
    Cerundolo V, Silk JD, Masri SH, Salio M. Harnessing invariant NKT cells in vaccination strategies. Nat Rev Immunol. 2009;9:28–38.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2009

Authors and Affiliations

  1. 1.Department of Hematology and OncologyGraduate School of Medicine, University of TokyoTokyoJapan

Personalised recommendations