Functions of T cells in asthma: more than just TH2 cells


Key Points

  • Several T cell subsets are involved in the development of the diseases we call asthma, not just T helper 2 (TH2) cells.

  • Emerging data describe the existence of innate immune cells that are capable of producing TH2-type cytokines and promoting TH2-type responses, even in the absence of T cells.

  • T cells are not always lineage committed but show plasticity within the local cytokine environment.

  • Environmental influences such as age, gender, obesity, infection history, atopic status, allergen exposure levels, antibiotic use, exposure to pollution, and nutrition (for example, levels of vitamin A, vitamin D and vitamin E and hormone exposure) contribute to the heterogeneity of clinical disease.

  • Cluster analysis shows distinct clinical phenotypes of asthma; these data are useful for designing therapeutic approaches that are tailored towards specific asthma symptoms.


Asthma has been considered a T helper 2 (TH2) cell-associated inflammatory disease, and TH2-type cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, are thought to drive the disease pathology in patients. Although atopic asthma has a substantial TH2 cell component, the disease is notoriously heterogeneous, and recent evidence has suggested that other T cells also contribute to the development of asthma. Here, we discuss the roles of different T cell subsets in the allergic lung, consider how each subset can contribute to the development of allergic pathology and evaluate how we might manipulate these cells for new asthma therapies.

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Figure 1: T cells involved in the induction of the allergic phenotype.
Figure 2: Alternative pathway to a TH2-type response in the airways.
Figure 3: T cell subset signatures are affected by a variety of genetic and environmental influences.


  1. 1

    Mosmann, T. R. & Coffman, R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv. Immunol. 46, 111–147 (1989).

    CAS  Article  Google Scholar 

  2. 2

    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  Google Scholar 

  3. 3

    Bentley, A. M. et al. Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am. Rev. Respir. Dis. 146, 500–506 (1992).

    CAS  Article  Google Scholar 

  4. 4

    Cohn, L., Elias, J. A. & Chupp, G. L. Asthma: mechanisms of disease persistence and progression. Annu. Rev. Immunol. 22, 789–815 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Finkelman, F. D., Hogan, S. P., Hershey, G. K. K., Rothenberg, M. E. & Wills-Karp, M. Importance of cytokines in murine allergic airway disease and human asthma. J. Immunol. 184, 1663–1674 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Saenz, S. A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Price, A. E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl Acad. Sci. USA 107, 11489–11494 (2010). References 7–10 are a series of landmark papers describing the populations of innate immune cells that are able to produce T H 2-type cytokines.

    CAS  Article  Google Scholar 

  11. 11

    Paul, W. E. & Zhu, J. How are TH2-type immune responses initiated and amplified? Nature Rev. Immunol. 10, 225–235 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Larche, M., Robinson, D. S. & Kay, A. B. The role of T lymphocytes in the pathogenesis of asthma. J. Allergy Clin. Immunol. 111, 450–463 (2003).

    CAS  Article  Google Scholar 

  13. 13

    Mamessier . et al. T-cell activation during exacerbations: a longitudinal study in refractory asthma. Allergy 63, 1202–1210 (2008).

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Boguniewicz, M. et al. The effects of nebulized recombinant interferon-γ in asthmatic airways. J. Allergy Clin. Immunol. 95, 133–135 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Haldar, P. & Pavord, I. D. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J. Allergy Clin. Immunol. 119, 1043–1052 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Alcorn, J. F., Crowe, C. R. & Kolls, J. K. TH17 Cells in Asthma and COPD. Annu. Rev. Physiol. 72, 495–516 (2010).

    CAS  Article  Google Scholar 

  22. 22

    Molet, S. et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J. Allergy Clin. Immunol. 108, 430–438 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Wisam, A. et al. TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 123, 1185–1187 (2009).

    Article  CAS  Google Scholar 

  24. 24

    Pene, J. et al. Chronically inflamed human tissues are infiltrated by highly differentiated TH17 lymphocytes. J. Immunol. 180, 7423–7430 (2008).

    CAS  Article  Google Scholar 

  25. 25

    He, R., Oyoshi, M. K., Jin, H. & Geha, R. S. Epicutaneous antigen exposure induces a TH17 response that drives airway inflammation after inhalation challenge. Proc. Natl Acad. Sci. USA 104, 15817–15822 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Wilson, R. H. et al. Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am. J. Respir. Crit. Care Med. 180, 720–730 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Wakashin, H. et al. IL-23 and TH17 cells enhance TH2 cell-mediated eosinophilic airway inflammation in mice. Am. J. Respir. Crit. Care Med. 178, 1023–1032 (2008).

    CAS  Article  Google Scholar 

  28. 28

    McKinley, L. et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181, 4089–4097 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Schnyder-Candrian, S. et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Murdoch, J. R. & Lloyd, C. M. Resolution of allergic airway inflammation and airway hyperreactivity is mediated by IL-17 producing γδ T cells. Am. J. Respir. Crit. Care Med. 182, 464–476 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Veldhoen, M. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunol. 9, 1341–1346 (2008). This paper provides evidence that T cells are not necessarily committed lineages and that there is plasticity among T cell subsets.

    CAS  Article  Google Scholar 

  33. 33

    Chang, H. C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nature Immunol. 11, 527–534 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Angkasekwinai, P., Chang, S. H., Thapa, M., Watarai, H. & Dong, C. Regulation of IL-9 expression by IL-25 signaling. Nature Immunol. 11, 250–256 (2010).

    CAS  Article  Google Scholar 

  35. 35

    Pejman, S. & Taylor, A. D. TH9 and allergic disease. Immunology 127, 450–458 (2009).

    Article  CAS  Google Scholar 

  36. 36

    Erpenbeck, V. J. et al. Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J. Allergy Clin. Immunol. 111, 1319–1327 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Shimbara, A. et al. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J. Allergy Clin. Immunol. 105, 108–115 (2000).

    CAS  Article  Google Scholar 

  38. 38

    Temann, U. A., Geba, G. P., Rankin, J. A. & Flavell, R. A. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188, 1307–1320 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    McMillan, S. J., Bishop, B., Townsend, M. J., McKenzie, A. N. & Lloyd, C. M. The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J. Exp. Med. 195, 51–57 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Ying, S. et al. Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J. Immunol. 158, 3539–3544 (1997).

    CAS  Google Scholar 

  41. 41

    Cho, S. H., Stanciu, L. A., Holgate, S. T. & Johnston, S. L. Increased interleukin-4, interleukin-5, and interferon-γ in airway CD4+ and CD8+ T cells in atopic asthma. Am. J. Respir. Crit. Care Med. 171, 224–230 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Hirosako, S. et al. CD8 and CD103 are highly expressed in asthmatic bronchial intraepithelial lymphocytes. Int. Arch. Allergy Immunol. 153, 157–165 (2010).

    CAS  Article  Google Scholar 

  43. 43

    Betts, R. J. & Kemeny, D. M. CD8+ T cells in asthma: friend or foe? Pharmacol. Ther. 121, 123–131 (2009).

    CAS  Article  Google Scholar 

  44. 44

    Laberge, S. et al. Depletion of CD8+ T cells enhances pulmonary inflammation but not airway responsiveness after antigen challenge in rats. J. Allergy Clin. Immunol. 98, 617–627 (1996).

    CAS  Article  Google Scholar 

  45. 45

    Isogai, S., Jedrzkiewicz, S., Taha, R., Hamid, Q. & Martin, J. G. Resident CD8+ T cells suppress CD4+ T cell-dependent late allergic airway responses. J. Allergy Clin. Immunol. 115, 521–526 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Tsuchiya, K. et al. Depletion of CD8+ T cells enhances airway remodelling in a rodent model of asthma. Immunology 126, 45–54 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Sawicka, E., Noble, A., Walker, C. & Kemeny, D. M. Tc2 cells respond to soluble antigen in the respiratory tract and induce lung eosinophilia and bronchial hyperresponsiveness. Eur. J. Immunol. 34, 2599–2608 (2004).

    CAS  Article  Google Scholar 

  48. 48

    Isogai, S. et al. CD8+ αβ T cells can mediate late airway responses and airway eosinophilia in rats. J. Allergy Clin. Immunol. 114, 1345–1352 (2004).

    CAS  Article  Google Scholar 

  49. 49

    Miyahara, N. et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nature Med. 10, 865–869 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Miyahara, N. et al. Contribution of antigen-primed CD8+ T cells to the development of airway hyperresponsiveness and inflammation is associated with IL-13. J. Immunol. 172, 2549–2558 (2004).

    CAS  Article  Google Scholar 

  51. 51

    Koya, T. et al. CD8+ T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4+IL-4+ T cells. J. Immunol. 179, 2787–2796 (2007).

    CAS  Article  Google Scholar 

  52. 52

    Coyle, A. J. et al. Virus-specific CD8+ cells can switch to interleukin 5 production and induce airway eosinophilia. J. Exp. Med. 181, 1229–1233 (1995).

    CAS  Article  Google Scholar 

  53. 53

    Corne, J. M. et al. Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study. Lancet 359, 831–834 (2002).

    Article  Google Scholar 

  54. 54

    van Rensen, E. L. et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am. J. Respir. Crit. Care Med. 172, 837–841 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    O'Sullivan, S. et al. Activated, cytotoxic CD8+ T lymphocytes contribute to the pathology of asthma death. Am. J. Respir. Crit. Care Med. 164, 560–564 (2001).

    CAS  Article  Google Scholar 

  56. 56

    Lloyd, C. M. & Hawrylowicz, C. M. Regulatory T cells in asthma. Immunity. 31, 438–449 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Ostroukhova, M. et al. Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3. J. Clin. Invest. 114, 28–38 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Kearley, J., Barker, J. E., Robinson, D. S. & Lloyd, C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J. Exp. Med. 202, 1539–1547 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Leech, M. D. et al. Resolution of Der p1-Induced allergic airway inflammation is dependent on CD4+CD25+Foxp3+ regulatory cells. J. Immunol. 179, 7050–7058 (2007).

    CAS  Article  Google Scholar 

  60. 60

    Joetham, A. et al. Naturally occurring lung CD4+CD25+ T cell regulation of airway allergic responses depends on IL-10 induction of TGF-β. J. Immunol. 178, 1433–1442 (2007).

    CAS  Article  Google Scholar 

  61. 61

    Strickland, D. H. et al. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells. J. Exp. Med. 203, 2649–2660 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Cederbom, L., Hall, H. & Ivars, F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol. 30, 1538–1543 (2000).

    CAS  Article  Google Scholar 

  63. 63

    Onishi, Y., Fehervari, Z., Yamaguchi, T. & Sakaguchi, S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc. Natl Acad. Sci. USA 105, 10113–10118 (2008).

    CAS  Article  Google Scholar 

  64. 64

    Lewkowich, I. P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Meiler, F. et al. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 205, 2887–2898 (2008). This paper shows that T cells can be successfully reprogrammed as a result of allergen immunotherapy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Ling, E. M. et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004).

    CAS  Article  Google Scholar 

  67. 67

    Bellinghausen, I., Klostermann, B., Knop, J. & Saloga, J. Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J. Allergy Clin. Immunol. 111, 862–868 (2003).

    CAS  Article  Google Scholar 

  68. 68

    Grindebacke, H. et al. Defective suppression of TH2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season. Clin. Exp. Allergy 34, 1364–1372 (2004).

    CAS  Article  Google Scholar 

  69. 69

    Lin, Y.-L., Shieh, C.-C. & Wang, J. Y. The functional insufficiency of human CD4+CD25+ T-regulatory cells in allergic asthma is subjected to TNF-α modulation. Allergy 63, 67–74 (2008).

    CAS  Article  Google Scholar 

  70. 70

    Hartl, D. et al. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J. Allergy Clin. Immunol. 119, 1258–1266 (2007).

    CAS  Article  Google Scholar 

  71. 71

    Khoa, D. N., Christopher, V., Alison, F. & Kari, C. N. Selective deregulation in chemokine signaling pathways of CD4+CD25hiCD127lo regulatory T cells in human allergic asthma. J. Allergy Clin. Immunol. 123, 933–939 (2009).

    Article  CAS  Google Scholar 

  72. 72

    Ryanna, K., Stratigou, V., Safinia, N. & Hawrylowicz, C. Regulatory T cells in bronchial asthma. Allergy 64, 335–347 (2009).

    CAS  Article  Google Scholar 

  73. 73

    Hawrylowicz, C. et al. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J. Allergy Clin. Immunol. 109, 369–370 (2002).

    CAS  Article  Google Scholar 

  74. 74

    Xystrakis, E. et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J. Clin. Invest. 116, 146–155 (2006).

    CAS  Article  Google Scholar 

  75. 75

    Sadlon, T. J. et al. Genome-wide identification of human FOXP3 target genes in natural regulatory T cells. J. Immunol. 185, 1071–1081 (2010).

    CAS  Article  Google Scholar 

  76. 76

    Feuerer, M., Hill, J. A., Mathis, D. & Benoist, C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nature Immunol. 10, 689–695 (2009).

    CAS  Article  Google Scholar 

  77. 77

    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  Google Scholar 

  78. 78

    Nagata, Y., Kamijuku, H., Taniguchi, M., Ziegler, S. & Seino, K. Differential role of thymic stromal lymphopoietin in the induction of airway hyperreactivity and Th2 immune response in antigen-induced asthma with respect to natural killer T cell function. Int. Arch. Allergy Immunol. 144, 305–314 (2007).

    CAS  Article  Google Scholar 

  79. 79

    Jae-Ouk, K. 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 

  80. 80

    Ponpan, M. et al. Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates. J. Allergy Clin. Immunol. 121, 1287–1289 (2008).

    Article  CAS  Google Scholar 

  81. 81

    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  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    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  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    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  Google Scholar 

  84. 84

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    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 

  86. 86

    Wands, J. M. et al. Distribution and leukocyte contacts of γδ T cells in the lung. J. Leukoc. Biol. 78, 1086–1096 (2005).

    CAS  Article  Google Scholar 

  87. 87

    Carding, S. R. & Egan, P. J. γδ T cells: functional plasticity and heterogeneity. Nature Rev. Immunol. 2, 336–345 (2002).

    CAS  Article  Google Scholar 

  88. 88

    Spinozzi, F. et al. Increased allergen-specific, steroid-sensitive γδ T cells in bronchoalveolar lavage fluid from patients with asthma. Ann. Intern. Med. 124, 223–227 (1996).

    CAS  Article  Google Scholar 

  89. 89

    Pawankar, R. U. et al. Phenotypic and molecular characteristics of nasal mucosal γδ T cells in allergic and infectious rhinitis. Am. J. Respir. Crit. Care Med. 153, 1655–1665 (1996).

    CAS  Article  Google Scholar 

  90. 90

    Lahn, M. et al. MHC class I-dependent Vγ4+ pulmonary T cells regulate αβ T cell-independent airway responsiveness. Proc. Natl Acad. Sci. USA 99, 8850–8855 (2002).

    CAS  Article  Google Scholar 

  91. 91

    Hahn, Y. S. et al. Vγ4+ γδ T cells regulate airway hyperreactivity to methacholine in ovalbumin-sensitized and challenged mice. J. Immunol. 171, 3170–3178 (2003).

    CAS  Article  Google Scholar 

  92. 92

    Born, W. et al. Immunoregulatory functions of γδ T cells. Adv. Immunol. 71, 77–144 (1999).

    CAS  Article  Google Scholar 

  93. 93

    Sather, B. D. et al. Altering the distribution of Foxp3+ regulatory T cells results in tissue-specific inflammatory disease. J. Exp. Med. 204, 1335–1347 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Annunziato, F. et al. Phenotypic and functional features of human TH17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Acosta-Rodriguez, E. V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature Immunol. 8, 639–646 (2007).

    CAS  Article  Google Scholar 

  96. 96

    Lim, H. W., Lee, J., Hillsamer, P. & Kim, C. H. Human TH17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J. Immunol. 180, 122–129 (2008).

    CAS  Article  Google Scholar 

  97. 97

    Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Julia, V. et al. A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure. Immunity. 16, 271–283 (2002).

    CAS  Article  Google Scholar 

  99. 99

    Constant, S. L. et al. Resident lung antigen-presenting cells have the capacity to promote TH2 T cell differentiation in situ. J. Clin. Invest. 110, 1441–1448 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3 effector T cells. Nature Immunol. 9, 1347–1355 (2008).

    CAS  Article  Google Scholar 

  101. 101

    Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 30, 92–107 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Moore, W. C. et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am. J. Respir. Crit. Care Med. 181, 315–323 (2009). This paper describes the results of hierarchical cluster analysis, which reveals distinct but overlapping clinical phenotypes in asthma; this should facilitate the development of new therapeutic approaches tailored towards specific patient groups.

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Lloyd, C. M. & Saglani, S. Asthma and allergy: the emerging epithelium. Nature Med. 16, 273–274 (2010).

    CAS  Article  Google Scholar 

  104. 104

    Woodruff, P. G. et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Natl Acad. Sci. USA 104, 15858–15863 (2007). This paper highlights the importance of epithelial gene expression as a driving force in asthma and describes potential epithelial gene signatures that predispose towards particular clinical phenotypes.

    CAS  Article  Google Scholar 

  105. 105

    Woodruff, P. G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Chen, G. et al. Foxa2 programs TH2 cell-mediated innate immunity in the developing lung. J. Immunol. 184, 6133–6141 (2010).

    CAS  Article  Google Scholar 

  107. 107

    Martinez, F. D. et al. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 332, 133–138 (2009).

    Article  Google Scholar 

  108. 108

    Holt, P. G., Strickland, D. H., Wikstrom, M. E. & Jahnsen, F. L. Regulation of immunological homeostasis in the respiratory tract. Nature Rev. Immunol. 8, 142–152 (2008).

    CAS  Article  Google Scholar 

  109. 109

    Haddeland, U. et al. Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatr. Allergy Immunol. 16, 104–112 (2005).

    Article  Google Scholar 

  110. 110

    Willers, S. M. et al. Maternal food consumption during pregnancy and the longitudinal development of childhood asthma. Am. J. Respir. Crit. Care Med. 178, 124–131 (2008).

    Article  Google Scholar 

  111. 111

    Litonjua, A. A. & Weiss, S. T. Is vitamin D deficiency to blame for the asthma epidemic? J. Allergy Clin. Immunol. 120, 1031–1035 (2007).

    CAS  Article  Google Scholar 

  112. 112

    Miller, R. L. Prenatal maternal diet affects asthma risk in offspring. J. Clin. Invest. 118, 3265–3268 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Holt, P. G., Upham, J. W. & Sly, P. D. Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies. J. Allergy Clin. Immunol. 116, 16–24 (2005).

    Article  Google Scholar 

  114. 114

    Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Ege, M. J. et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J. Allergy Clin. Immunol. 117, 817–823 (2006).

    Article  Google Scholar 

  116. 116

    Bianca, S. et al. Impairment of T-regulatory cells in cord blood of atopic mothers. J. Allergy Clin. Immunol. 121, 1491–1499 (2008).

    Article  CAS  Google Scholar 

  117. 117

    Conrad, M. L. et al. Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J. Exp. Med. 206, 2869–2877 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Barnes, P. J. New therapies for asthma: is there any progress? Trends Pharmacol. Sci. 31, 335–343 (2010).

    CAS  Article  Google Scholar 

  119. 119

    Partridge, M., van der Molen, T., Myrseth, S. E. & Busse, W. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm. Med. 6, 13 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Gamble, J., Stevenson, M., McClean, E. & Heaney, L. G. The prevalence of nonadherence in difficult asthma. Am. J. Respir. Crit. Care Med. 180, 817–822 (2009).

    Article  Google Scholar 

  121. 121

    Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 (2000).

    CAS  Article  Google Scholar 

  122. 122

    Kips, J. C. et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am. J. Respir. Crit. Care Med. 167, 1655–1659 (2003).

    Article  Google Scholar 

  123. 123

    O'Byrne, P. M. The demise of anti IL-5 for asthma, or not. Am. J. Respir. Crit. Care Med. 176, 1059–1060 (2007).

    Article  Google Scholar 

  124. 124

    Nair, P. et al. Mepolizumab for prednisone-dependent asthma with Sputum Eosinophilia. N. Engl. J. Med. 360, 985–993 (2009).

    CAS  Article  Google Scholar 

  125. 125

    Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009). References 124 and 125 describe the results from clinical trials in which patients were preselected on the basis of a specific asthma phenotype: the authors show that this improves the efficacy of treatment.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Suzana, R., Mikila, R. J., Stephen, R. D. & Kayhan, T. N. A. Grass pollen immunotherapy induces Foxp3-expressing CD4+CD25+ cells in the nasal mucosa. J. Allergy Clin. Immunol. 121, 1467–1472 (2008).

    Article  CAS  Google Scholar 

  127. 127

    Akdis, M. & Akdis, C. A. Therapeutic manipulation of immune tolerance in allergic disease. Nature Rev. Drug Discov. 8, 645–660 (2009).

    CAS  Article  Google Scholar 

  128. 128

    Stephen, R. D. et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J. Allergy Clin. Immunol. 125, 131–138 (2010).

    Article  CAS  Google Scholar 

  129. 129

    Peek, E. J. et al. Interleukin-10-secreting “regulatory” T cells induced by glucocorticoids and β2-agonists. Am. J. Respir. Cell. Mol. Biol. 33, 105–111 (2005).

    CAS  Article  Google Scholar 

  130. 130

    Xirakia, C. et al. Toll-like receptor 7-triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma. Am. J. Respir. Crit. Care Med. 181, 1207–1216 (2010).

    CAS  Article  Google Scholar 

  131. 131

    Hessel, E. M. et al. Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting TH2 cell activation and IgE-mediated cytokine induction. J. Exp. Med. 202, 1563–1573 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Sur, S. et al. Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides. J. Immunol. 162, 6284–6293 (1999).

    CAS  Google Scholar 

  133. 133

    Gauvreau, G. M., Hessel, E. M., Boulet, L. P., Coffman, R. L. & O'Byrne, P. M. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses. Am. J. Respir. Crit. Care Med. 174, 15–20 (2006).

    CAS  Article  Google Scholar 

  134. 134

    Meri, K. T. et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J. Allergy Clin. Immunol. 113, 235–241 2004.

    Article  CAS  Google Scholar 

  135. 135

    Asai, K. et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy increases CD4+CD25+ T cells in the nasal mucosa of subjects with allergic rhinitis. Allergol. Int. 57, 377–381 (2008).

    CAS  Article  Google Scholar 

  136. 136

    Fort, M. M. et al. IL-25 Induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985–995 (2001).

    CAS  Article  PubMed  Google Scholar 

  137. 137

    Kondo, Y. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol. 20, 791–800 (2008).

    CAS  Article  Google Scholar 

  138. 138

    Mattes, J., Yang, M. & Foster, P. S. Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function? Am. J. Respir. Cell. Mol. Biol. 36, 8–12 (2007).

    CAS  Article  Google Scholar 

  139. 139

    Mattes, J., Collison, A., Plank, M., Phipps, S. & Foster, P. S. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc. Natl Acad. Sci. USA 106, 18704–18709 (2009).

    CAS  Article  Google Scholar 

  140. 140

    Polikepahad, S. et al. Pro-inflammatory role for let-7 microRNAs in experimental asthma. J. Biol. Chem. 285, 30139–30149 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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The authors acknowledge R. Coffman for his critical reading and input, A. Calver for his contribution to the supplementary information and K. Alexander for her help with the manuscript.

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Correspondence to Clare M. Lloyd.

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Edith M. Hessel has been employed by GlaxoSmithKline since July 2009.

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Airway hyperresponsiveness

(AHR). A hyperreactivity of the airways, initiated by exposure to a defined stimulus that is usually tolerated by normal individuals; it causes bronchoconstriction and inflammatory-cell infiltration in allergic individuals. This is a defining physiological characteristic of asthma.

Forced expiratory volume in 1 second

(FEV1). A primary indicator of lung function.

Hygiene hypothesis

This hypothesis originally proposed that the increased incidence of atopic diseases in westernized countries was a consequence of living in an overly clean environment, resulting in an under-stimulated immune system that responded inappropriately to harmless antigens. More recently it has been proposed that an absence of exposure to pathogens, in particular helminths, may predispose to both increased allergy and autoimmune disease.


A class of medication aimed at dilating the airways by the agonism of the β-adrenoreceptor pathway.

Allergen-specific immunotherapy

Allergen immunotherapy was introduced in the early 1900s. In general, it involves subcutaneous injection of increasing doses of specific allergen into the patient. This is carried out under carefully controlled clinical conditions because of the potential for life-threatening adverse reactions. On average, it results in 50% reduction of clinical symptoms and medication usage, and it also results in beneficial modifications of the patient's immune response to allergen. Following the initial course of injections (either conventional or rushed), patients receive maintenance injections (less frequently) of allergen for optimal clinical benefit.


Small, non-coding RNA molecules that regulate the expression of several genes by binding to the 3′ untranslated regions of specific mRNAs.

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Lloyd, C., Hessel, E. Functions of T cells in asthma: more than just TH2 cells. Nat Rev Immunol 10, 838–848 (2010).

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