Current Allergy and Asthma Reports

, Volume 5, Issue 5, pp 356–361

The role of the FOXP3 transcription factor in the immune regulation of allergic asthma

  • Carsten B. Schmidt-Weber
  • Kurt Blaser


Unbalanced immune reactions against allergens are caused by Th2 cells, which are the basis of immunoglobulin E (IgE)-mediated symptoms of allergy and asthma. Although Th2 cells are essential for allergy, they are not sufficient to cause disease, because regulatory T cells (Tregs) control their activity and expansion. Therefore, Tregs are assumed to play an important role not only in the sensitization but also in established allergic disease under therapy. A key factor of Tregs is FOXP3, which, upon expression, is sufficient to induce regulatory T-cell phenotypes. The initiation and suppressive function of FOXP3 and Tregs in the context of allergic asthma are discussed in this review.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    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. This article shows the difference in T-cell frequency of healthy and allergic individuals. The frequency of IL-10—secreting T cells is demonstrated to be significantly higher in healthy subjects than in allergic subjects.PubMedCrossRefGoogle Scholar
  2. 2.
    Schmidt-Weber CB, Blaser K: Immunological mechanisms in specific immunotherapy. Springer Semin Immunopathol 2004, 25:377–390. This review provides an overview of specific immunotherapies; possible mechanisms are summarized.PubMedCrossRefGoogle Scholar
  3. 3.
    Schmidt-Weber CB, Blaser K: Immunological mechanisms of specific allergen immunotherapy. Curr Drug Targets Inflamm Allergy 2004, In press.Google Scholar
  4. 4.
    Groux H, O’Garra A, Bigler M, et al.: A CD4(+) T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997, 389:737–742.PubMedCrossRefGoogle Scholar
  5. 5.
    Weiner HL: Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001, 182:207–214.PubMedCrossRefGoogle Scholar
  6. 6.
    Hori S, Takahashi T, Sakaguchi S: Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 2003, 81:331–371.PubMedGoogle Scholar
  7. 7.
    Liang S, Alard P, Zhao Y, et al.: Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 2005, 201:127–137.PubMedCrossRefGoogle Scholar
  8. 8.
    Kasprowicz DJ, Smallwood PS, Tyznik AJ, Ziegler SF: Scurfin (FoxP3) controls T-dependent immune responses in vivo through regulation of CD4+ T cell effector function. J Immunol 2003, 171:1216–1223.PubMedGoogle Scholar
  9. 9.
    Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057–1061.PubMedCrossRefGoogle Scholar
  10. 10.
    Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 2003, 4:330–336.PubMedCrossRefGoogle Scholar
  11. 11.
    Coffer PJ, Burgering BM: Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 2004, 4:889–899.PubMedCrossRefGoogle Scholar
  12. 12.
    Chatila TA, Blaeser F, Ho N, et al.: JM2, encoding a forkheadrelated protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 2000, 106:R75-R81.PubMedCrossRefGoogle Scholar
  13. 13.
    Wildin RS, Ramsdell F, Peake J, et al.: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001, 27:18–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Schubert LA, Jeffery E, Zhang Y, et al.: Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 2001, 276:37672–37679.PubMedCrossRefGoogle Scholar
  15. 15.
    Bettelli E, Dastrange M, Oukka M: Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci U S A 2005, 102:5138–5143.PubMedCrossRefGoogle Scholar
  16. 16.
    Lai JH, Horvath G, Subleski J, et al.: RelA is a potent transcriptional activator of the CD28 response element within the interleukin 2 promoter. Mol Cell Biol 1995, 15:4260–4271.PubMedGoogle Scholar
  17. 17.
    Kahn-Perles B, Lipcey C, Lecine P, et al.: Temporal and subunitspecific modulations of the Rel/NF-kappaB transcription factors through CD28 costimulation. J Biol Chem 1997, 272:21774–21783.PubMedCrossRefGoogle Scholar
  18. 18.
    Jenkins MK, Chen CA, Jung G, et al.: Inhibition of antigenspecific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J Immunol 1990, 144:16–22. Classic study on the basic mechanisms on T-cell anergy, which is still a valid basis for knowledge of suppressive mechanisms.PubMedGoogle Scholar
  19. 19.
    Bour-Jordan H, Salomon BL, Thompson HL, et al.: Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells. J Clin Invest 2004, 114:979–987.PubMedCrossRefGoogle Scholar
  20. 20.
    Lin CH, Hunig T: Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 2003, 33:626–638.PubMedCrossRefGoogle Scholar
  21. 21.
    Takeda I, Ine S, Killeen N, et al.: Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol 2004, 172:3580–3589.PubMedGoogle Scholar
  22. 22.
    Masuyama J, Kaga S, Kano S, Minota S: A novel costimulation pathway via the 4C8 antigen for the induction of CD4+ regulatory T cells. J Immunol 2002, 169:3710–3716.PubMedGoogle Scholar
  23. 23.
    Read S, Malmstrom V, Powrie F: Cytotoxic T lymphocyteassociated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000, 192:295–302.PubMedCrossRefGoogle Scholar
  24. 24.
    Tang Q, Boden EK, Henriksen KJ, et al.: Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol 2004, 34:2996–3005.PubMedCrossRefGoogle Scholar
  25. 25.
    Kataoka H, Takahashi S, Takase K, et al.: CD25(+)CD4(+) regulatory T cells exert in vitro suppressive activity independent of CTLA-4. Int Immunol 2005, 17:421–427.PubMedCrossRefGoogle Scholar
  26. 26.
    Faith A, Akdis CA, Akdis M, et al.: Defective TCR stimulation in anergized type 2 T-helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities. J Immunol 1997, 159:53–60.PubMedGoogle Scholar
  27. 27.
    Huang CT, Workman CJ, Flies D, et al.: Role of LAG-3 in regulatory T cells. Immunity 2004, 21:503–513. Important and convincing data showing that MHC-pathways (“signal 1”) contribute to Treg-mediated suppression. It is shown that anti-LAG-3 (CD223) as well as genetically induced CD223-defects affect Treg-mediated suppression.PubMedCrossRefGoogle Scholar
  28. 28.
    Akdis CA, Blaser K: Mechanisms of interleukin-10-mediated immune suppression. Immunology 2001, 103:131–136.PubMedCrossRefGoogle Scholar
  29. 29.
    Joss A, Akdis M, Faith A, et al.: IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol 2000, 30:1683–1690.PubMedCrossRefGoogle Scholar
  30. 30.
    Frasca L, Carmichael P, Lechler R, Lombardi G: Anergic T cells effect linked suppression. Eur J Immunol 1997, 27:3191–3197.PubMedCrossRefGoogle Scholar
  31. 31.
    Holan V, Mitchison NA: Haplotype-specific suppressor T cells mediating linked suppression of immune responses elicited by third-party H-2 alloantigens. Eur J Immunol 1983, 13:652–657.PubMedCrossRefGoogle Scholar
  32. 32.
    Vendetti S, Chai JG, Dyson J, et al.: Anergic T cells inhibit the antigen-presenting function of dendritic cells. J Immunol 2000, 165:1175–1181.PubMedGoogle Scholar
  33. 33.
    Karagiannidis C, Akdis M, Holopainen P, et al.: Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 2004, 114:1425–1433. This publication shows that established drugs such as GC may be useful to support the endogenous capability of the organism to control inflammation. It also shows the effect of drugs and cytokines on the generation of Tregs in vitro.PubMedCrossRefGoogle Scholar
  34. 34.
    Schmidt-Weber CB, Blaser K: Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol 2004, 16:709–716. This review attempts to integrate the immunologic and regenerative functions of TGF-β. Relevant signaling pathways are discussed.PubMedCrossRefGoogle Scholar
  35. 35.
    Chen TC, Cobbold SP, Fairchild PJ, Waldmann H: Generation of anergic and regulatory T cells following prolonged exposure to a harmless antigen. J Immunol 2004, 172:5900–5907. This work supports the hypothesis of Treg induction as a default pathway in the absence of decision signals. Previous work of this group gave evidence of regulatory cells before the discovery of CD25+ Tregs (see "infectious tolerance").PubMedGoogle Scholar
  36. 36.
    Godfrey WR, Spoden DJ, Ge YG, et al.: Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 2005, 105:750–758.PubMedCrossRefGoogle Scholar
  37. 37.
    Fantini MC, Becker C, Monteleone G, et al.: Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25-T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004, 172:5149–5153.PubMedGoogle Scholar
  38. 38.
    Marie JC, Letterio JJ, Gavin M, Rudensky AY: TGF-{beta}1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 2005, 201:1061–1067.PubMedCrossRefGoogle Scholar
  39. 39.
    Gorelik L, Flavell RA: Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2002, 2:46–53.PubMedCrossRefGoogle Scholar
  40. 40.
    Gorelik L, Fields PE, Flavell RA: Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 2000, 165:4773–4777.PubMedGoogle Scholar
  41. 41.
    Heath VL, Murphy EE, Crain C, et al.: TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol 2000, 30:2639–2649.PubMedCrossRefGoogle Scholar
  42. 42.
    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. This article describes the effect of a cytokine involved in acute phase reactions and its impact on the specific immune system. Interestingly, it could be demonstrated that CD4+CD25+ but not CD4+CD25-lung T cells selectively expressed the IL-6R alpha chain.PubMedCrossRefGoogle Scholar
  43. 43.
    Kemper C, Chan AC, Green JM, et al.: Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 2003, 421:388–392.PubMedCrossRefGoogle Scholar
  44. 44.
    Gorczynski RM, Lee L, Boudakov I: Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R. Transplantation 2005, 79:488–491.PubMedCrossRefGoogle Scholar
  45. 45.
    Vasu C, Prabhakar BS, Holterman MJ: Targeted CTLA-4 engagement induces CD4+CD25+CTLA-4high T regulatory cells with target (allo)antigen specificity. J Immunol 2004, 173:2866–2876.PubMedGoogle Scholar
  46. 46.
    Sinclair NR: Why so many coinhibitory receptors? Scand J Immunol 1999, 50:10–13.PubMedCrossRefGoogle Scholar
  47. 47.
    von Bubnoff D, Fimmers R, Bogdanow M, et al.: Asymptomatic atopy is associated with increased indoleamine 2,3-dioxygenase activity and interleukin-10 production during seasonal allergen exposure. Clin Exp Allergy 2004, 34:1056–1063.CrossRefGoogle Scholar
  48. 48.
    Ling EM, Smith T, Nguyen XD, 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 2004, 363:608–615. The data presented in this paper reveal that not only the frequency but also the activity of Tregs may play an important role in the pathogenesis of allergy.PubMedCrossRefGoogle Scholar
  49. 49.
    Shi HZ, Li S, Xie ZF, et al.: Regulatory CD4+CD25+ T lymphocytes in peripheral blood from patients with atopic asthma. Clin Immunol 2004, 113:172–178.PubMedCrossRefGoogle Scholar
  50. 50.
    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.PubMedCrossRefGoogle Scholar
  51. 51.
    Nguyen XD, Robinson DS: Fluticasone propionate increases CD4+CD25+ T regulatory cell suppression of allergen-stimulated CD4+CD25-T cells by an IL-10-dependent mechanism. J Allergy Clin Immunol 2004, 114:296–301. This article complements data shown in Karagiannidis et al. [33] and shows that GCs do not diminish Treg-mediated suppression.CrossRefGoogle Scholar
  52. 52.
    Bousquet J, Demoly P, Michel FB: Specific immunotherapy in rhinitis and asthma. Ann Allergy Asthma Immunol 2001, 87:38–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Stock P, Akbari O, Berry G, et al.: Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol 2004, 5:1149–1156. Important study confirming that Tregs can, in fact, modulate the severity of airway inflammation.PubMedCrossRefGoogle Scholar
  54. 54.
    Jutel M, Akdis M, Budak F, et al.: IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003, 33:1205–1214.PubMedCrossRefGoogle Scholar
  55. 55.
    Kitani A, Fuss I, Nakamura K, et al.: Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGFbeta1-mediated fibrosis. J Exp Med 2003, 198:1179–1188.PubMedCrossRefGoogle Scholar
  56. 56.
    Yamamoto T, Eckes B, Krieg T: Effect of interleukin-10 on the gene expression of type I collagen, fibronectin, and decorin in human skin fibroblasts: differential regulation by transforming growth factor-beta and monocyte chemoattractant protein-1. Biochem Biophys Res Commun 2001, 281:200–205.PubMedCrossRefGoogle Scholar
  57. 57.
    Arai T, Abe K, Matsuoka H, et al.: Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am J Physiol Lung Cell Mol Physiol 2000, 278:L914-L922.PubMedGoogle Scholar
  58. 58.
    Moroguchi A, Ishimura K, Okano K, et al.: Interleukin-10 suppresses proliferation and remodeling of extracellular matrix of cultured human skin fibroblasts. Eur Surg Res 2004, 36:39–44.PubMedCrossRefGoogle Scholar
  59. 59.
    Carlsson P, Mahlapuu M: Forkhead transcription factors: key players in development and metabolism. Dev Biol 2002, 250:1–23.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Carsten B. Schmidt-Weber
    • 1
  • Kurt Blaser
    • 1
  1. 1.Swiss Institute of Allergy and Asthma Research (SIAF)DavosSwitzerland

Personalised recommendations