iNKT Cells in Allergic Disease

  • E. H. Meyer
  • R. H. DeKruyff
  • D. T. Umetsu
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 314)


Natural Killer Atopic Dermatitis Allergic Disease iNKT Cell Contact Sensitivity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Umetsu DT, McIntire JJ, Akbari O, Macaubus C, DeKruyff RH (2002) Asthma: an epidemic of dysregulated immunity. Nat Immunol 3:715–720PubMedCrossRefGoogle Scholar
  2. 2.
    Mannino DM, Homa DM, Pertowski CA et al (1998) Surveillance for asthma — United States, 1960–1995. MMWR CDC Surveill Summ 47:1–27PubMedGoogle Scholar
  3. 3.
    McNally N, Philips D, Williams H (1998) The problem of atopic eczema: aetiological clues from the environment and lifestyles. Soc Sci Med 46:729–741PubMedCrossRefGoogle Scholar
  4. 4.
    Blumenthal J, Blumenthal MN (1996) Immunogenetics of allergy and asthma. Immunol Allergy Clin North Am 16:517–534CrossRefGoogle Scholar
  5. 5.
    Weiss KB, Sullivan SD (2001) The health economics of asthma and rhinitis. I. Asssessing the economic impact. J Allergy Clin Immunol 107:3–8PubMedCrossRefGoogle Scholar
  6. 6.
    Zaas D, Schwartz DA (2003) Genetics of environmental asthma. Semin Respir Crit Care Med 24:185–195PubMedCrossRefGoogle Scholar
  7. 7.
    McIntire JJ, Umetsu DT, DeKruyff RH (2004) TIM-1, a novel allergy and asthma susceptibility gene. Springer Semin Immunopathol 25:335–348PubMedCrossRefGoogle Scholar
  8. 8.
    Blumenthal MN (2005) The role of genetics in the development of asthma and atopy. Curr Opin Allergy Clin Immunol 5:141–145PubMedGoogle Scholar
  9. 9.
    McIntire JJ et al (2005) Hepatitis A virus link to atopic disease. Nature 425:576CrossRefGoogle Scholar
  10. 10.
    Umetsu SE, Lee WL, McIntire JJ et al (2005) TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nat Immunol 6:447–454PubMedCrossRefGoogle Scholar
  11. 11.
    Maizels RM (2005) Infections and allergy—helminths, hygiene and host immune regulation. Curr Opin Immunol 17:656–661PubMedCrossRefGoogle Scholar
  12. 12.
    Blaser K (2004) Allergy and hypersensitivity—From genes to phenotype—Editorial overview. Curr Opin Immunol 16:685–688PubMedCrossRefGoogle Scholar
  13. 13.
    Upham JW, Holt PG (2005) Environment and development of atopy. Curr Opin Allergy Clin Immunol 5:167–172PubMedCrossRefGoogle Scholar
  14. 14.
    Kay AB (2001) Advances in immunology: allergy and allergic diseases: first of two parts. N Engl J Med 344:30–37PubMedCrossRefGoogle Scholar
  15. 15.
    Kay AB (2001) Advances in immunology—allergy and allergic diseases—second of two parts. N Engl J Med 344:109–113PubMedCrossRefGoogle Scholar
  16. 16.
    Akbari O et al (2006) CD4+ invariant T-cell-receptor plus natural killer T cells in bronchial asthma. N Engl J Med 354:1117–1129PubMedCrossRefGoogle Scholar
  17. 17.
    Akbari O et al (2003) Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 9:582–588PubMedCrossRefGoogle Scholar
  18. 18.
    Lisbonne M et al (2003) Cutting edge: invariant V alpha 14. NKT cells dare required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J Immunol 171:1637–1641PubMedGoogle Scholar
  19. 19.
    Mannino DM et al (2002) Surveillance for asthma — United States 1980–1999. MMWR CDC Surveill Summ 51:1Google Scholar
  20. 20.
    Herrick CA, Bottomly K (2003) To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol 3:405–412PubMedCrossRefGoogle Scholar
  21. 21.
    Robinson DS et al (1992) Predominant Th2-like bronchoalveolar lymphocyte-t population in atopic asthma. N Engl J Med 326:298–304PubMedCrossRefGoogle Scholar
  22. 22.
    Meyer EH et al (2006) Glycolipid activation of invariant T cell receptor(+) NKT cells is sufficient to induce airway hyperreactivity independent of conventional CD4(+) T cells. Proc Natl Acad Sci U S A 103:2782–2787PubMedCrossRefGoogle Scholar
  23. 23.
    Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) Opinion—NKT cells: what’s in a name? Nat Rev Immunol 4:231–237PubMedCrossRefGoogle Scholar
  24. 24.
    Taniguchi M, Harada M, Kojo S, Nakayama T, Wakao H (2003) The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Ann Rev Immunol 21:483CrossRefGoogle Scholar
  25. 25.
    Brigl M, Brenner MB (2004) CD1: antigen presentation and T cell function. Ann Rev Immunol 2:557Google Scholar
  26. 26.
    Kinjo Y et al (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520–525PubMedCrossRefGoogle Scholar
  27. 27.
    Zhou DP et al (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786–1789PubMedCrossRefGoogle Scholar
  28. 28.
    Kronenberg M (2005) Toward an understanding of NKT cell biology: progress and paradoxes. Ann Rev Immunol 23:877–900CrossRefGoogle Scholar
  29. 29.
    Exley MA, Koziel MJ (2004) To be or not to be NKT: natural killer T cells in the liver. Hepatology 40:1033–1040PubMedCrossRefGoogle Scholar
  30. 30.
    Seino K, Taniguchi M (2005) Functionally distinct NKT cell subsets and subtypes. J Exp Med 202:1623–1626PubMedCrossRefGoogle Scholar
  31. 31.
    Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114:1379–1388PubMedCrossRefGoogle Scholar
  32. 32.
    Mattner J et al (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529PubMedCrossRefGoogle Scholar
  33. 33.
    Zeng DF et al (1999) Bone marrow NK1.1-and NK1.1+ T cells reciprocally regulate acute graft versus host disease. J Exp Med 189:1073–1081PubMedCrossRefGoogle Scholar
  34. 34.
    Crowe NY et al (2005) Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med 202:1279–1288PubMedCrossRefGoogle Scholar
  35. 35.
    Cui JQ et al (1999) Inhibition of T helper cell type 2 cell differentiation and immunoglobulin E response by ligand-activated Valpha14 natural killer T cells. J Exp Med 190:783–792PubMedCrossRefGoogle Scholar
  36. 36.
    Korsgren M et al (1999) Natural killer cell determine development of allergen-induced eosinophilic airway inflammation in mice. J Exp Med 189:553–562PubMedCrossRefGoogle Scholar
  37. 37.
    Brown DR et al (1996) Beta-2-microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses. J Exp Med 184:1295–1304PubMedCrossRefGoogle Scholar
  38. 38.
    Zhang Y, Rogers KH, Lewis DB (1996) Beta-2-microglobulin-dependent T cells are dispensable for allergen-induced T helper 2 responses. J Exp Med 184:1507–1512PubMedCrossRefGoogle Scholar
  39. 39.
    Kim HS et al (1999) Biochemical characterization of CD1d expression in the absence of beta(2)-microglobulin. J Biol Chem 274:9289–9295PubMedCrossRefGoogle Scholar
  40. 40.
    Amano M et al (1998) CD1 expression defines subsets of follicular and marginal zone B cells in the spleen: beta(2)-microglobulin-dependent and independent forms. J Immunol 161:1710–1717PubMedGoogle Scholar
  41. 41.
    Maeda M, Shadeo A, MacFadyen AM, Takei F (2004) CD1d-independent NKT cells in beta(2)-microglobulin-deficient mice have hybrid phenotype and function of NK and T cells. J Immunol 172:6115–6122PubMedGoogle Scholar
  42. 42.
    Smiley ST, Kaplan MH, Grusby MJ (1997) Immunoglobulin E production in the absence of interleukin-4-secreting CD1-dependent cells. Sci (Washington DC) 275:977–979CrossRefGoogle Scholar
  43. 43.
    Kim JO et al (2004) Asthma is induced by intranasal coadministration of allergen and natural killer T-cell ligand in a mouse model. J Allergy Clin Immunol 114:1332–1338PubMedCrossRefGoogle Scholar
  44. 44.
    Yoshimoto T, Bendelac A, Watson C, Hu-Li K, Paul W (1995) Role of NK1.1+ T cells in Th2 responses and in immunoglobulin E production. Science 270:1845–1847PubMedCrossRefGoogle Scholar
  45. 45.
    Vonderweid T, Beebe AM, Roopenian DC, Coffman RL (1996) Early production of IL-4 and induction of Th2 responses in the lymph node originate from an MHC class I-independent CD4(+)NK1.1(−)T cell population. J Immunol 157:4421–4427Google Scholar
  46. 46.
    Yoshimoto T, Bendelac A, Huli J, Paul WE (1995) 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 U S A 92:11931–11934PubMedCrossRefGoogle Scholar
  47. 47.
    Bendelac A, Hunziker RD, Lantz O (1996) Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells. J Exp Med 184:1285–1293PubMedCrossRefGoogle Scholar
  48. 48.
    Mattner J et al (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529PubMedCrossRefGoogle Scholar
  49. 49.
    Stein-Streilein J (2003) Invariant NKT cells as initiators, licensors, and facilitators of the adaptive immune response. J Exp Med 198:1779–1783PubMedCrossRefGoogle Scholar
  50. 50.
    Lin M, Rikihisa Y (2003) Erlichia chaffeensis and Anaplasma phaocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival. Infect Immun 71:5325Google Scholar
  51. 51.
    Trottein F, Mallevaey T, Faveeuw C, Capron M, Leite-de-Moraes M (2006) Role of the natural killer T lymphocyte in Th2 responses during allergic asthma and helminth parasitic diseases. Chem Immunol Allergy 90:113–127PubMedCrossRefGoogle Scholar
  52. 52.
    Mallevaey T et al (2006) Activation of invariant NKT cells by the helminth parasite g1 Schistosoma mansoni. J Immunol 176:2476–2485PubMedGoogle Scholar
  53. 53.
    Agea E et al (2005) Human CD1-restricted T cell recognition of lipids from pollens. J Exp Med 202:295–308PubMedCrossRefGoogle Scholar
  54. 54.
    Ikegami Y, Yokoyama A, Haruta Y, Hiyama K, Kohno N (2004) Circulating natural killer T cells in patients with asthma. J Asthma 41:877–882PubMedCrossRefGoogle Scholar
  55. 55.
    Sen Y et al (2005) V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3(+) T cells upon CD226 engagement. J Immunol 175:4914–4926PubMedGoogle Scholar
  56. 56.
    Milner JD et al (1999) Differential responses of invariant V alpha 24J alpha QT cells and MHC class II-restricted CD4(+) T cells to dexamethasone. J Immunol 163:2522–2529PubMedGoogle Scholar
  57. 57.
    Tamada K, Harada M, Abe K, Li TL, Nomoto K (1998) IL-4-producing NK1.1(+) T cells are resistant to glucocorticoid-induced apoptosis: implications for the Th1/Th2 balance. J Immunol 161:1239–1247PubMedGoogle Scholar
  58. 58.
    Adcock IM, Ito K (2004) Steroid resistance in asthma: a major problem requiring novel solutions or a non-issue? Curr Opin Pharmacol 4:257–262PubMedCrossRefGoogle Scholar
  59. 59.
    Ito K, Chung KF, Adcock IM (2006) Update on glucocorticoid action and resistance. J Allergy Clin Immunol 117:522–543PubMedCrossRefGoogle Scholar
  60. 60.
    Hachem P et al (2005) Alpha-galactosylceramide-induced iNKT cells suppress experimental allergic asthma in sensitized mice: role of IFN-gamma. Eur J Immunol 35:2793–2802PubMedCrossRefGoogle Scholar
  61. 61.
    Matsuda H et al (2005) Alpha-galactosylceramide, a ligand of natural killer T cells, inhibits allergic airway inflammation. Am J Respir Cell Mol Biol 33:22–31PubMedCrossRefGoogle Scholar
  62. 62.
    Morishima Y et al (2005) Suppression of eosinophilic airway inflammation by treatment with alpha-galactosylceramide. Eur J Immunol 35:2803–2814PubMedCrossRefGoogle Scholar
  63. 63.
    Parekh VV, Wilson MT, Van Kaer L (2005) iNKT-cell responses to glycolipids. Crit Rev Immunol 25:183–213PubMedCrossRefGoogle Scholar
  64. 64.
    Matsuda JL et al (2003) Mouse V alpha 14i natural killer T cells are resistant to cytokine polarization in vivo. Proc Natl Acad Sci U S A 100:8395–8400PubMedCrossRefGoogle Scholar
  65. 65.
    Wang ZY et al (2006) Regulation of Th2 cytokine expression in NKT cells: unconventional use of Stat6, GATA-3, and NFAT2. J Immunol 176:880–888PubMedGoogle Scholar
  66. 66.
    Sherman MA, Secor VH, Lee SK, Lopez RD, Brown MA (1999) STAT6-independent production of IL-4 by mast cells. Eur J Immunol 29:1235–1242PubMedCrossRefGoogle Scholar
  67. 67.
    Kim CH, Johnston B, Butcher EC (2002) Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity. Blood 100:11–16PubMedCrossRefGoogle Scholar
  68. 68.
    Gumperz JE, Miyake S, Yamamura T, Brenner MB (2002) Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med 195:625–636PubMedCrossRefGoogle Scholar
  69. 69.
    Matsuda JL et al (2001) Natural killer T cells reactive to a single glycolipid exhibit a highly diverse T cell receptor beta repertoire and small clone size. Proc Natl Acad Sci U S A 98:12636–12641PubMedCrossRefGoogle Scholar
  70. 70.
    Johnston B et al (2003) Differential chemokine responses and homing patterns of murine TCR alpha beta NKT cell subsets. J Immunol 171:2960–2969PubMedGoogle Scholar
  71. 71.
    Mi QS, Ly D, Zucker P, McGarry M, Delovitch TL (2004) Interleukin-4 but not interleukin-10 protects against spontaneous and recurrent type 1 diabetes by activated CD1d-restricted invariant natural killer T-cells. Diabetes 53:1303–1310PubMedCrossRefGoogle Scholar
  72. 72.
    Sharif S et al (2001) Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nat Med 7:1057–1062PubMedCrossRefGoogle Scholar
  73. 73.
    Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A (2002) A thymic precursor to the NKT cell lineage. Science 296:481–482CrossRefGoogle Scholar
  74. 74.
    MacDonald HR (2002) Development and selection of NKT cells. Curr Opin Immunol 14:250–254PubMedCrossRefGoogle Scholar
  75. 75.
    Schmieg J, Yang GL, Franck RW, Tsuji M (2003) Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-galactosylceramide. J Exp Med 198:1631–1641PubMedCrossRefGoogle Scholar
  76. 76.
    Schmieg J, Yang GG, Franck RW, Van Rooijen NV, Tsuji M (2005) Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc Natl Acad Sci U S A 102:1127–1132PubMedCrossRefGoogle Scholar
  77. 77.
    Bezbradica JS et al (2005) Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo. J Immunol 174:4696–4705PubMedGoogle Scholar
  78. 78.
    Fujii SI, Liu K, Smith C, Bonito AJ, Steinman RM (2004) The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med 199:1607–1618PubMedCrossRefGoogle Scholar
  79. 79.
    Fujii S, Shimizu K, Kronenberg M, Steinman RM (2002) Prolonged IFN-gamma-producing NKT response induced with alpha-galactosylceramide-loaded DCs. Nat Immunol 3:867–874PubMedCrossRefGoogle Scholar
  80. 80.
    Lan FS, Zeng DF, Higuchi M, Higgins JP, Strober S (2003) 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 9:355–363PubMedCrossRefGoogle Scholar
  81. 81.
    Lowsky R et al (2005) Protective conditioning for acute graft-versus-host disease. N Engl J Med 353:1321–1331PubMedCrossRefGoogle Scholar
  82. 82.
    Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638PubMedCrossRefGoogle Scholar
  83. 83.
    Kaser A et al (2004) Natural killer T cells in mucosal homeostasis. In: Weiner H, Mayer L, Strober W (eds) Oral tolerance: new insights and prospects for clinical application. Ann N Y Acad Sci 1029:154–168Google Scholar
  84. 84.
    Hopkin JM (1997) Mechanisms of enhanced prevalence of asthma and atopy in developed countries. Curr Opin Immunol 9:788–792PubMedCrossRefGoogle Scholar
  85. 85.
    Campos RA et al (2003) Cutaneous immunization rapidly activates liver invariant V alpha-14. NKT cells stimulating B-1B cells to initiate T cell recruitment for elicitation of contact sensitivity. J Exp Med 198:1785–1796PubMedCrossRefGoogle Scholar
  86. 86.
    Nieuwenhuis EES et al (2005) CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol 14:250–258PubMedCrossRefGoogle Scholar
  87. 87.
    Oishi Y et al (2000) CD4(−)CD8(−) T cells bearing invariant V alpha 24J alpha QTCR alpha-chain are decreased in patients with atopic diseases. Clin Exp Immunol 119:404–411PubMedCrossRefGoogle Scholar
  88. 88.
    Takahashi T et al (2003) Valpha 24(+) natural killer T cells are markedly decreased in atopic dermatitis patients. Hum Immunol 64:586–592PubMedGoogle Scholar
  89. 89.
    Magnan A et al (2000) Relationships between natural T cells, atopy IgE levels, and IL-4 production. Allergy (Copenhagen) 55:286–290CrossRefGoogle Scholar
  90. 90.
    Saubermann LJ et al (2000) Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice. Gastroenterology 119:119–128PubMedCrossRefGoogle Scholar
  91. 91.
    Fuss IJ et al (2004) Nonclassical CD1d-restricted NKT cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • E. H. Meyer
    • 1
    • 2
  • R. H. DeKruyff
    • 1
  • D. T. Umetsu
    • 1
  1. 1.Division of Immunology, Children’s Hospital BostonHarvard Medical SchoolBostonUSA
  2. 2.Immunology Program and the Department of PediatricsStanford UniversityStanfordUSA

Personalised recommendations