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.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mosmann, T. R. & Coffman, R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv. Immunol. 46, 111–147 (1989).
Robinson, D. S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
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).
Cohn, L., Elias, J. A. & Chupp, G. L. Asthma: mechanisms of disease persistence and progression. Annu. Rev. Immunol. 22, 789–815 (2004).
Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).
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).
Saenz, S. A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
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.
Paul, W. E. & Zhu, J. How are TH2-type immune responses initiated and amplified? Nature Rev. Immunol. 10, 225–235 (2010).
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).
Mamessier . et al. T-cell activation during exacerbations: a longitudinal study in refractory asthma. Allergy 63, 1202–1210 (2008).
Finotto, S. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295, 336–338 (2002).
Boguniewicz, M. et al. The effects of nebulized recombinant interferon-γ in asthmatic airways. J. Allergy Clin. Immunol. 95, 133–135 (1995).
Haldar, P. & Pavord, I. D. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J. Allergy Clin. Immunol. 119, 1043–1052 (2007).
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).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005).
Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
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).
Alcorn, J. F., Crowe, C. R. & Kolls, J. K. TH17 Cells in Asthma and COPD. Annu. Rev. Physiol. 72, 495–516 (2010).
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).
Wisam, A. et al. TH17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol. 123, 1185–1187 (2009).
Pene, J. et al. Chronically inflamed human tissues are infiltrated by highly differentiated TH17 lymphocytes. J. Immunol. 180, 7423–7430 (2008).
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).
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).
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).
McKinley, L. et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181, 4089–4097 (2008).
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).
Schnyder-Candrian, S. et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203, 2715–2725 (2006).
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).
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.
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).
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).
Pejman, S. & Taylor, A. D. TH9 and allergic disease. Immunology 127, 450–458 (2009).
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).
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).
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).
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).
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).
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).
Hirosako, S. et al. CD8 and CD103 are highly expressed in asthmatic bronchial intraepithelial lymphocytes. Int. Arch. Allergy Immunol. 153, 157–165 (2010).
Betts, R. J. & Kemeny, D. M. CD8+ T cells in asthma: friend or foe? Pharmacol. Ther. 121, 123–131 (2009).
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).
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).
Tsuchiya, K. et al. Depletion of CD8+ T cells enhances airway remodelling in a rodent model of asthma. Immunology 126, 45–54 (2009).
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).
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).
Miyahara, N. et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nature Med. 10, 865–869 (2004).
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).
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).
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).
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).
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).
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).
Lloyd, C. M. & Hawrylowicz, C. M. Regulatory T cells in asthma. Immunity. 31, 438–449 (2009).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
Ryanna, K., Stratigou, V., Safinia, N. & Hawrylowicz, C. Regulatory T cells in bronchial asthma. Allergy 64, 335–347 (2009).
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).
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).
Sadlon, T. J. et al. Genome-wide identification of human FOXP3 target genes in natural regulatory T cells. J. Immunol. 185, 1071–1081 (2010).
Feuerer, M., Hill, J. A., Mathis, D. & Benoist, C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nature Immunol. 10, 689–695 (2009).
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).
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).
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).
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).
Vijayanand, P. et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 1410–1422 (2007).
Akbari, O. et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117–1129 (2006).
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).
Matangkasombut, P. et al. Natural killer T cells in the lungs of patients with asthma. J. Allergy Clin. Immunol. 123, 1181–1185 (2009).
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).
Wands, J. M. et al. Distribution and leukocyte contacts of γδ T cells in the lung. J. Leukoc. Biol. 78, 1086–1096 (2005).
Carding, S. R. & Egan, P. J. γδ T cells: functional plasticity and heterogeneity. Nature Rev. Immunol. 2, 336–345 (2002).
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).
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).
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).
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).
Born, W. et al. Immunoregulatory functions of γδ T cells. Adv. Immunol. 71, 77–144 (1999).
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).
Annunziato, F. et al. Phenotypic and functional features of human TH17 cells. J. Exp. Med. 204, 1849–1861 (2007).
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).
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).
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).
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).
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).
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).
Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 30, 92–107 (2009).
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.
Lloyd, C. M. & Saglani, S. Asthma and allergy: the emerging epithelium. Nature Med. 16, 273–274 (2010).
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.
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).
Chen, G. et al. Foxa2 programs TH2 cell-mediated innate immunity in the developing lung. J. Immunol. 184, 6133–6141 (2010).
Martinez, F. D. et al. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 332, 133–138 (2009).
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).
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).
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).
Litonjua, A. A. & Weiss, S. T. Is vitamin D deficiency to blame for the asthma epidemic? J. Allergy Clin. Immunol. 120, 1031–1035 (2007).
Miller, R. L. Prenatal maternal diet affects asthma risk in offspring. J. Clin. Invest. 118, 3265–3268 (2008).
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).
Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).
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).
Bianca, S. et al. Impairment of T-regulatory cells in cord blood of atopic mothers. J. Allergy Clin. Immunol. 121, 1491–1499 (2008).
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).
Barnes, P. J. New therapies for asthma: is there any progress? Trends Pharmacol. Sci. 31, 335–343 (2010).
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).
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).
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).
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).
O'Byrne, P. M. The demise of anti IL-5 for asthma, or not. Am. J. Respir. Crit. Care Med. 176, 1059–1060 (2007).
Nair, P. et al. Mepolizumab for prednisone-dependent asthma with Sputum Eosinophilia. N. Engl. J. Med. 360, 985–993 (2009).
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.
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).
Akdis, M. & Akdis, C. A. Therapeutic manipulation of immune tolerance in allergic disease. Nature Rev. Drug Discov. 8, 645–660 (2009).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
Polikepahad, S. et al. Pro-inflammatory role for let-7 microRNAs in experimental asthma. J. Biol. Chem. 285, 30139–30149 (2010).
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.
Edith M. Hessel has been employed by GlaxoSmithKline since July 2009.
- 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.
About this article
Cite this article
Lloyd, C., Hessel, E. Functions of T cells in asthma: more than just TH2 cells. Nat Rev Immunol 10, 838–848 (2010). https://doi.org/10.1038/nri2870
Cellular Immunology (2020)
Sargassum horneri extract containing mojabanchromanol attenuates the particulate matter exacerbated allergic asthma through reduction of Th2 and Th17 response in mice
Environmental Pollution (2020)
Biochemical Pharmacology (2020)
Therapeutic and prophylactic deletion of IL‐4Ra‐signaling ameliorates established ovalbumin induced allergic asthma