Skip to main content

Interleukin-10-Secreting regulatory T cells in allergy and asthma

Abstract

Allergic diseases, including asthma, are chronic inflammatory disorders originating from an aberrant immune response to innocuous antigens in our environment (allergens). In susceptible individuals, sensitization to allergen leads to the induction of allergen-specific Thelper type 2 (Th2) responses and immunoglobulin E (IgE) production. Subsequent challenge with allergen results in IgE-mediated mast cell activation and the recruitment and activation of effector cells, leading to clinical symptoms of disease. In this review, we discuss evidence that the anti-inflammatory cytokine interleukin-10 (IL-10) offers therapeutic promise for the control of asthma and allergy. We highlight the potential role of IL-10 secretion by a specialized T-cell subset, T regulatory cells, to prevent allergic inflammation in healthy individuals and to provide long-term relief from disease symptoms in allergic patients.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

  1. Robinson DS, Hamid Q, Ying S, et al.: Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992, 326:298–304.

    PubMed  CAS  Article  Google Scholar 

  2. Romagnani S: Regulation of the development of type 2 T-helper cells in allergy. Curr Opin Immunol 1994, 6:838–846.

    PubMed  Article  CAS  Google Scholar 

  3. Gershon RK, Kondo K: Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 1970, 18:723–737.

    PubMed  CAS  Google Scholar 

  4. Schmidt-Weber CB, Kunzmann S, Blaser K: TGF-betamediated control of allergen-specific T-cell responses. Curr Allergy Asthma Rep 2002, 2:259–262.

    PubMed  Article  Google Scholar 

  5. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA: Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006, 24:99–146.

    PubMed  Article  CAS  Google Scholar 

  6. Shevach E: CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2004, 2:389–400.

    Google Scholar 

  7. Sakaguchi S: Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004, 22:531–562.

    PubMed  Article  CAS  Google Scholar 

  8. Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003, 4:330–336.

    PubMed  Article  CAS  Google Scholar 

  9. Khattri R, Cox T, Yasayko SA, Ramsdell F: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003, 4:337–342.

    PubMed  Article  CAS  Google Scholar 

  10. Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057–1061.

    PubMed  Article  CAS  Google Scholar 

  11. Fontenot JD, Rasmussen JP, Williams LM, et al.: Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005, 22:329–341.

    PubMed  Article  CAS  Google Scholar 

  12. O’Garra A, Vieira P: Regulatory T cells and mechanisms of immune system control. Nat Med 2004, 10:801–805.

    PubMed  Article  CAS  Google Scholar 

  13. Hawrylowicz CM, O’Garra A: Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 2005, 5:271–283.

    PubMed  Article  CAS  Google Scholar 

  14. Hawrylowicz CM: Regulatory T cells and IL-10 in allergic inflammation. J Exp Med 2005, 202:1459–1463.

    PubMed  Article  CAS  Google Scholar 

  15. Robinson DS: The role of regulatory T lymphocytes in asthma pathogenesis. Curr Allergy Asthma Rep 2005, 5:136–141.

    PubMed  Article  CAS  Google Scholar 

  16. Chatila TA, Blaeser F, Ho N, et al.: JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunityallergic dysregulation syndrome. J Clin Invest 2000, 106:R75-R81.

    PubMed  CAS  Google Scholar 

  17. Ling EM, Smith T, Nguyen XD, et al.: Relation of CD4+CD25+ regulatory T-cell suppression of allergendriven T-cell activation to atopic status and expression of allergic disease. Lancet 2004, 363:608–615. Evidence that the naturally occurring CD4+CD25+ Treg compartment inhibits and prevents Th2 responses to ubiquitous allergens in healthy individuals

    PubMed  Article  CAS  Google Scholar 

  18. Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003, 299:1033–1036.

    PubMed  Article  CAS  Google Scholar 

  19. Ruprecht CR, Gattorno M, Ferlito F, et al.: Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J Exp Med 2005, 201:1793–1803.

    PubMed  Article  CAS  Google Scholar 

  20. Doganci A, Eigenbrod T, Krug N, et al.: The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 2005, 115:313–325.

    PubMed  Article  CAS  Google Scholar 

  21. Grindebacke H, Wing K, Andersson AC, et al.: Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season. Clin Exp Allergy 2004, 34:1364–1372.

    PubMed  Article  CAS  Google Scholar 

  22. 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 2003, 111:862–868.

    PubMed  Article  CAS  Google Scholar 

  23. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001, 19:683–765.

    PubMed  Article  CAS  Google Scholar 

  24. Asadullah K, Sterry W, Volk HD: Interleukin-10 therapy—review of a new approach. Pharmacol Rev 2003, 55:241–269. A comprehensive review and bibliography relating to the biology of and clinical studies with IL-10.

    PubMed  Article  CAS  Google Scholar 

  25. Grunig G, Corry DB, Leach MW, et al.: Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J Exp Med 1997, 185:1089–1099.

    PubMed  Article  CAS  Google Scholar 

  26. Tournoy KG, Kips JC, Pauwels RA: Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness. Clin Exp Allergy 2000, 30:775–783.

    PubMed  Article  CAS  Google Scholar 

  27. Akdis M, Verhagen J, Taylor A, et al.: Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 2004, 199:1567–1575. A study suggesting a high IL-10 to IL-4 ratio of allergen responsive T cells in the peripheral blood of healthy donors, as compared to allergic patients, may be important in the maintenance of immune homeostasis and prevention of inappropriate response to allergen.

    PubMed  Article  CAS  Google Scholar 

  28. John M, Lim S, Seybold J, et al.: Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma. Am J Respir Crit Care Med 1998, 157:256–262.

    PubMed  CAS  Google Scholar 

  29. Borish L, Aarons A, Rumbyrt J, et al.: Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol 1996, 97:1288–1296.

    PubMed  Article  CAS  Google Scholar 

  30. Heaton T, Rowe J, Turner S, et al.: An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 2005, 365:142–149. A study, together with John et al. [28], Borish et al. [29], and Lim et al. [31], suggesting an inverse correlation between IL-10 levels and the incidence and/or severity of allergic and asthmatic disease.

    PubMed  Article  CAS  Google Scholar 

  31. Lim S, Crawley E, Woo P, Barnes PJ: Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 1998, 352:113.

    PubMed  Article  CAS  Google Scholar 

  32. Bacchetta R, Bigler M, Touraine JL, et al.: High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994, 179:493–502.

    PubMed  Article  CAS  Google Scholar 

  33. Groux H, O’Garra A, Bigler M, et al.: Generation of a novel regulatory CD4+ T-cell population, which inhibits antigenspecific T-cell responses. Nature 1997, 389:737–742.

    PubMed  Article  CAS  Google Scholar 

  34. Levings MK, Sangregorio R, Galbiati F, et al.: IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001, 166:5530–5539.

    PubMed  CAS  Google Scholar 

  35. McGuirk P, McCann C, Mills KH: Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 2002, 195:221–231.

    PubMed  Article  CAS  Google Scholar 

  36. Sundstedt A, O’Neill EJ, Nicolson KS, Wraith DC: Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol 2003, 170:1240–1248.

    PubMed  CAS  Google Scholar 

  37. Jonuleit H, Schmitt E, Schuler G, et al.: Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 2000, 192:1213–1222.

    PubMed  Article  CAS  Google Scholar 

  38. Brinkmann V, Kristofic C: Regulation by corticosteroids of Th1 and Th2 cytokine production in human CD4+ effector T cells generated from CD45RO- and CD45RO+ subsets. J Immunol 1995, 155:3322–3328.

    PubMed  CAS  Google Scholar 

  39. Richards DF, Fernandez M, Caulfield J, Hawrylowicz CM: Glucocorticoids drive human CD8(+) T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production. Eur J Immunol 2000, 30:2344–2354.

    PubMed  Article  CAS  Google Scholar 

  40. Barrat FJ, Cua DJ, Boonstra A, et al.: In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002, 195:603–616.

    PubMed  Article  CAS  Google Scholar 

  41. Xystrakis E, Kusumakar S, Boswell S, et al.: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006, 116:146–155. This study, together with Hawrylowicz et al. [60], demonstrates that a poor clinical response to glucocorticoids correlates with poor in vitro glucocorticoid induction of IL-10 synthesis.

    PubMed  Article  CAS  Google Scholar 

  42. Peek EJ, Richards DF, Faith A, et al.: Interleukin-10 secreting ‘regulatory’ T cells induced by glucocorticoids and beta2-agonists. Am J Respir Cell Mol Biol 2005, 33:105–111.

    PubMed  Article  CAS  Google Scholar 

  43. Lloyd CM, Gonzalo JA, Coyle AJ, Gutierrez-Ramos JC: Mouse models of allergic airway disease. Adv Immunol 2001, 77:263–295.

    PubMed  CAS  Article  Google Scholar 

  44. Cottrez F, Hurst SD, Coffman RL, Groux H: T regulatory cells 1 inhibit a Th2-specific response in vivo. J Immunol 2000, 165:4848–4853.

    PubMed  CAS  Google Scholar 

  45. Oh JW, Seroogy CM, Meyer EH, et al.: CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation. J Allergy Clin Immunol 2002, 110:460–468.

    PubMed  Article  CAS  Google Scholar 

  46. Akbari O, Freeman GJ, Meyer EH, et al.: Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002, 8:1024–1032.

    PubMed  Article  CAS  Google Scholar 

  47. Stampfli MR, Cwiartka M, Gajewska BU, et al.: Interleukin-10 gene transfer to the airway regulates allergic mucosal sensitization in mice. Am J Respir Cell Mol Biol 1999, 21:586–596.

    PubMed  CAS  Google Scholar 

  48. Kearley J, Barker JE, Robinson DS, Lloyd CM: Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 2005, 202:1539–1547.

    PubMed  Article  CAS  Google Scholar 

  49. Dieckmann D, Bruett CH, Ploettner H, et al.: Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med 2002, 196:247–253.

    PubMed  Article  CAS  Google Scholar 

  50. Bellinghausen I, Metz G, Enk AH, et al.: Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur J Immunol 1997, 27:1131–1139.

    PubMed  Article  CAS  Google Scholar 

  51. Akdis CA, Blesken, Akdis, M., Wuthrich, B., and Blaser, K.: Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 1998, 102:98–106.

    PubMed  CAS  Google Scholar 

  52. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R: Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based crosssectional study. Lancet 2001, 357:752–756.

    PubMed  Article  CAS  Google Scholar 

  53. Jeannin P, Lecoanet S, Delneste Y, et al.: IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 1998, 160:3555–3561.

    PubMed  CAS  Google Scholar 

  54. Strait RT, Morris SC, Finkelman FD: IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J Clin Invest 2006, 116:833–841.

    PubMed  Article  CAS  Google Scholar 

  55. Till SJ, Francis JN, Nouri-Aria K, Durham SR: Mechanisms of immunotherapy. J Allergy Clin Immunol 2004, 113:1025–1034; quiz 1035.

    PubMed  Article  CAS  Google Scholar 

  56. Kuehr J, Brauburger J, Zielen S, et al.: Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin Immunol 2002, 109:274–280.

    PubMed  Article  CAS  Google Scholar 

  57. Novak N, Bieber T, Katoh N: Engagement of Fc epsilon RI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells. J Immunol 2001, 167:797–804.

    PubMed  CAS  Google Scholar 

  58. Larche M, Wraith DC: Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat Med 2005, 11:S69–76.

    PubMed  Article  CAS  Google Scholar 

  59. Verhoef A, Alexander C, Kay AB, Larche M: T cell epitope immunotherapy induces a CD4+ T cell population with regulatory activity. PLoS Med 2005, 2:e78.

    PubMed  Article  CAS  Google Scholar 

  60. Hawrylowicz C, Richards D, Loke TK, et al.: A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol 2002, 109:369–370.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Catherine M. Hawrylowicz BSc, PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Urry, Z., Xystrakis, E. & Hawrylowicz, C.M. Interleukin-10-Secreting regulatory T cells in allergy and asthma. Curr Allergy Asthma Rep 6, 363–371 (2006). https://doi.org/10.1007/s11882-996-0005-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-996-0005-8

Keywords

  • Asthma
  • Treg Cell
  • Allergy Clin Immunol
  • Allergen Immunotherapy
  • Allergic Bronchopulmonary Aspergillosis