Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

A role for natural killer T cells in asthma

Nature Reviews Immunology volume 6, pages 953–958 (2006)Cite this article

Abstract

In several mouse models, natural killer T cells have recently been found to be required for the development of airway hyper-reactivity, a cardinal feature of asthma. Moreover, in patients with chronic asthma, natural killer T cells with a T-helper-2-like phenotype (that is, that express CD4 and produce T helper 2 cytokines) are present in the lungs in large numbers. In this Opinion article, we suggest that natural killer T cells, which express a restricted T-cell receptor and respond to glycolipids rather than protein antigens, have a previously unsuspected but crucial role, distinct from that of T helper 2 cells, in the pathogenesis of asthma.

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: The relationship between T helper 2 cells and T-helper-2-like invariant natural killer T cells.
Figure 2: How natural killer T cells fit in with the current model of asthma.

Similar content being viewed by others

References

  1. Kon, O. M. et al. The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur. Respir. J. 18, 45–52 (2001).

    Article  CAS  Google Scholar 

  2. Gavett, S. H., Chen, X., Finkelman, F. & Wills-Karp, M. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am. J. Respir. Cell Mol. Biol. 10, 587–593 (1994).

    Article  CAS  Google Scholar 

  3. Azzawi, M. et al. Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am. Rev. Respir. Dis. 142, 1407–1413 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Hansen, G., Berry, G., DeKruyff, R. H. & Umetsu, D. T. Allergen-specific TH1 cells fail to counterbalance TH2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).

    Article  CAS  Google Scholar 

  6. Randolph, D. A., Carruthers, C. J., Szabo, S. J., Murphy, K. M. & Chaplin, D. D. Modulation of airway inflammation by passive transfer of allergen-specific TH1 and TH2 cells in a mouse model of asthma. J. Immunol. 162, 2375–2383 (1999).

    CAS  PubMed  Google Scholar 

  7. Cohn, L., Tepper, J. S. & Bottomly, K. IL-4-independent induction of airway hyperresponsiveness by TH2, but not TH1, cells. J. Immunol. 161, 3813–3816 (1998).

    CAS  PubMed  Google Scholar 

  8. Corry, D. B. et al. Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice. Mol. Med. 4, 344–355 (1998).

    Article  CAS  Google Scholar 

  9. Godfrey, D. I. & Kronenberg, M. Going both ways: immune regulation via CD1d-dependent NKT cells. J. Clin. Invest. 114, 1379–1388 (2004).

    Article  CAS  Google Scholar 

  10. Taniguchi, M., Harada, M., Kojo, S., Nakayama, T. & Wakao, H. The regulatory role of Vα14 NKT cells in innate and acquired immune response. Annu. Rev. Immunol. 21, 483–513 (2003).

    Article  CAS  Google Scholar 

  11. Exley, M. A. & Koziel, M. J. To be or not to be NKT: natural killer T cells in the liver. Hepatology 40, 1033–1040 (2004).

    Article  Google Scholar 

  12. Seino, K. & Taniguchi, M. Functionally distinct NKT cell subsets and subtypes. J. Exp. Med. 202, 1623–1626 (2005).

    Article  CAS  Google Scholar 

  13. Fuss, I. J. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical TH2 response in ulcerative colitis. J. Clin. Invest. 113, 1490–1497 (2004).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).

    Article  CAS  Google Scholar 

  18. Kinjo, Y. et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005).

    Article  CAS  Google Scholar 

  19. Zhou, D. P. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004).

    Article  CAS  Google Scholar 

  20. Kronenberg, M. & Rudensky, A. Regulation of immunity by self-reactive T cells. Nature 435, 598–604 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Lowsky, R. et al. Protective conditioning for acute graft-versus-host disease. N. Engl. J. Med. 353, 1321–1331 (2005).

    Article  CAS  Google Scholar 

  25. Zeng, D. et al. Activation of natural killer T cells in NZB/W mice induces TH1-type immune responses exacerbating lupus. J. Clin. Invest. 112, 1211–1222 (2003).

    Article  CAS  Google Scholar 

  26. Bilenki, L., Yang, J., Fan, Y., Wang, S. & Yang, X. Natural killer T cells contribute to airway eosinophilic inflammation induced by ragweed through enhanced IL-4 and eotaxin production. Eur. J. Immunol. 34, 345–354 (2004).

    Article  CAS  Google Scholar 

  27. Cui, J. et al. Inhibition of T helper cell type 2 cell differentiation and immunoglobulin E response by ligand-activated Vα14 natural killer T cells. J. Exp. Med. 190, 783–792 (1999).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Yoshimoto, T., Bendelac, A., Hu-Li, J. & Paul, W. E. 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).

    Article  CAS  Google Scholar 

  30. Kim, J. O. et al. Asthma is induced by intranasal coadministration of allergen and natural killer T-cell ligand in a mouse model. J. Allergy Clin. Immunol. 114, 1332–1338 (2004).

    Article  CAS  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. 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).

    Article  CAS  Google Scholar 

  33. Yoshimoto, T., Bendelac, A., Watson, C., Hu-Li, J. & Paul, W. E. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science 270, 1845–1847 (1995).

    Article  CAS  Google Scholar 

  34. Galli, G. et al. Innate immune responses support adaptive immunity: NKT cells induce B cell activation. Vaccine 21 (Suppl. 2), 48–54 (2003).

    Article  Google Scholar 

  35. Korsgren, M. et al. Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J. Exp. Med. 189, 553–562 (1999).

    Article  CAS  Google Scholar 

  36. Brown, D. et al. β2-Microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses. J. Exp. Med. 184, 1295–1304 (1996).

    Article  CAS  Google Scholar 

  37. Zhang, Y., Rogers, K. H. & Lewis, D. B. β2-Microglobulin-dependent T cells are dispensable for allergen-induced T helper 2 responses. J. Exp. Med. 184, 1507–1512 (1996).

    Article  CAS  Google Scholar 

  38. Amano, M. et al. CD1 expression defines subsets of follicular and marginal zone B cells in the spleen: β2-microglobulin-dependent and independent forms. J. Immunol. 161, 1710–1717 (1998).

    CAS  PubMed  Google Scholar 

  39. Maeda, M., Shadeo, A., MacFadyen, A. & Takei, F. CD1d-independent NKT cells in β2-microglobulin-deficient mice have hybrid phenotype and function of NK and T cells. J. Immunol. 172, 6115–6122 (2004).

    Article  CAS  Google Scholar 

  40. Kim, H. S. et al. Biochemical characterization of CD1d expression in the absence of β2-microglobulin. J. Biol. Chem. 274, 9289–9295 (1999).

    Article  CAS  Google Scholar 

  41. Townsend, M. J. et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity 20, 477–494 (2004).

    Article  CAS  Google Scholar 

  42. Finotto, S. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295, 336–338 (2002).

    Article  CAS  Google Scholar 

  43. Benlagha, K., Kyin, T., Beavis, A., Teyton, L. & Bendelac, A. A thymic precursor to the NK T cell lineage. Science 296, 553–555 (2002).

    Article  CAS  Google Scholar 

  44. 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  Google Scholar 

  45. Ikegami, Y., Yokoyama, A., Haruta, Y., Hiyama, K. & Kohno, N. Circulating natural killer T cells in patients with asthma. J. Asthma 41, 877–882 (2004).

    Article  CAS  Google Scholar 

  46. 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).

    Article  CAS  Google Scholar 

  47. 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  Google Scholar 

  48. Johnston, B., Kim, C., Soler, D., Emoto, M. & Butcher, E. Differential chemokine responses and homing patterns of murine TCRαβ NKT cell subsets. J. Immunol. 171, 2960–2969 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. Agea, E. et al. Human CD1-restricted T cell recognition of lipids from pollens. J. Exp. Med. 202, 295–308 (2005).

    Article  CAS  Google Scholar 

  51. Adcock, I. M. & Ito, K. Steroid resistance in asthma: a major problem requiring novel solutions or a non-issue? Curr. Opin. Pharmacol. 4, 257–262 (2004).

    Article  CAS  Google Scholar 

  52. Ito, K., Chung, K. F. & Adcock, I. M. Update on glucocorticoid action and resistance. J. Allergy Clin. Immunol. 117, 522–543 (2006).

    Article  CAS  Google Scholar 

  53. Milner, J. D. et al. Differential responses of invariant Vα24JαQ T cells and MHC class II-restricted CD4+ T cells to dexamethasone. J. Immunol. 163, 2522–2529 (1999).

    CAS  PubMed  Google Scholar 

  54. Tamada, K., Harada, M., Abe, K., Li, T. & Nomoto, K. IL-4-producing NK1.1+ T cells are resistant to glucocorticoid-induced apoptosis: implications for the TH1/TH2 balance. J. Immunol. 161, 1239–1247 (1998).

    CAS  PubMed  Google Scholar 

  55. Hachem, P. et al. α-Galactosylceramide-induced iNKT cells suppress experimental allergic asthma in sensitized mice: role of IFN-γ. Eur. J. Immunol. 35, 2793–2802 (2005).

    Article  CAS  Google Scholar 

  56. Matsuda, H. et al. α-Galactosylceramide, a ligand of natural killer T cells, inhibits allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 33, 22–31 (2005).

    Article  CAS  Google Scholar 

  57. Morishima, Y. et al. Suppression of eosinophilic airway inflammation by treatment with α-galactosylceramide. Eur. J. Immunol. 35, 2803–2814 (2005).

    Article  CAS  Google Scholar 

  58. Parekh, V. V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Invest. 115, 2572–2583 (2005).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. the Division of Immunology, Department of Pediatrics, Children's Hospital Boston, Harvard Medical School, 1 Blackfan Circle, Boston, 02115, Massachusetts, USA

    Dale T. Umetsu & Rosemarie H. DeKruyff

Authors
  1. Dale T. Umetsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosemarie H. DeKruyff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dale T. Umetsu.

Ethics declarations

Competing interests

Dale Umetsu is a consultant for Innate Immune Inc. (United States).

Related links

Related links

FURTHER INFORMATION

Dale Umetsu's homepage at Harvard University

Dale Umetsu's homepage at the Children's Hospital Boston

Rights and permissions

Reprints and permissions

About this article

Cite this article

Umetsu, D., DeKruyff, R. A role for natural killer T cells in asthma. Nat Rev Immunol 6, 953–958 (2006). https://doi.org/10.1038/nri1968

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1968

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