Current Allergy and Asthma Reports

, Volume 5, Issue 1, pp 35–41

CD25+ T cells and regulation of allergen-induced responses

  • Marina Ostroukhova
  • Anuradha Ray
Article

Abstract

CD4 T helper 2 (Th2) cells, with the characteristic interleukin (IL)-4, IL-5, and IL-13 cytokine secretion profile, play an important role in the initiation and perpetuation of allergic airways disease. It is clear from recent studies that CD4+ T cells with distinct cytokine-producing abilities have regulatory functions that limit allergic inflammation. Studies of allergic airway inflammation in mice have identified different types of T regulatory cells (Tregs) that control the disease phenotype. The cytokines associated with the Treg phenotype in mice include both soluble and cell membrane-bound transforming growth factor (TGF)-β and IL-10. Both contact-dependent mechanisms involving membrane-bound TGF-β and contactindependent mechanisms involving soluble TGF-β and IL-10 have been invoked to describe the function of these Tregs. In humans, studies of milk allergy show an association between circulating CD4+CD25+ Tregs and tolerance to the causative allergen, β-lactoglobulin. The identification of Tregs as suppressors of allergic disease may promote the development of new therapeutic strategies.

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References and Recommended Reading

  1. 1.
    Corrigan CJ, Hartnell A, Kay AB: T lymphocyte activation in acute severe asthma. Lancet 1988, 1:1129–1132.PubMedCrossRefGoogle Scholar
  2. 2.
    Azzawi M, Bradley B, Jeffrey PK, et al.: Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable asthmatics. Am Rev Respir Dis 1990, 142:1407–1413.PubMedGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhang D-H, Cohn L, Ray P, et al.: Transcription factor GATA-3 is differentially expressed in Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 1997, 272:21597–21603.PubMedCrossRefGoogle Scholar
  5. 5.
    Zheng W, Flavell RA: The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997, 89:587–596.PubMedCrossRefGoogle Scholar
  6. 6.
    Nakamura Y, Ghaffar O, Olivenstein R, et al.: Gene expression of the GATA-3 transcription factor is increased in atopic asthma. J Allergy Clin Immunol 1999, 103:215–222.PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang DH, Yang L, Cohn L, et al.: Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. Immunity 1999, 11:473–482.PubMedCrossRefGoogle Scholar
  8. 8.
    Cohn L, Elias JA:Chupp GL: Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 2004, 22:789–815.PubMedCrossRefGoogle Scholar
  9. 9.
    Mannino DM, Homa DM, Akinbami LJ, et al.: Surveillance for asthma—United States, 1980–1999. MMWR Surveill Summ 2002, 51:1–13.Google Scholar
  10. 10.
    Strachan DP: Hay fever, hygiene, and household size. BMJ 1989, 299:1259–1260.PubMedCrossRefGoogle Scholar
  11. 11.
    Matricardi PM, Franzinelli F, Franco A, et al.: Sibship size, birth order, and atopy in 11,371 Italian young men. J Allergy Clin Immunol 1998, 101:439–444.PubMedCrossRefGoogle Scholar
  12. 12.
    Ball TM, Castro-Rodriguez JA, Griffith KA, et al.: Siblings, daycare attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000, 343:538–543.PubMedCrossRefGoogle Scholar
  13. 13.
    Shirakawa T, Enomoto T, Shimazu S, Hopkin JM: The inverse association between tuberculin responses and atopic disorder. Science 1997, 275:77–79.PubMedCrossRefGoogle Scholar
  14. 14.
    Jacobson DL, Gange SJ, Rose NR, Graham NM: Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997, 84:223–243.PubMedCrossRefGoogle Scholar
  15. 15.
    McIntire JJ, Umetsu SE, Akbari O, et al.: Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2001, 2:1109–1116.PubMedCrossRefGoogle Scholar
  16. 16.
    McIntire JJ, Umetsu SE, Macaubas C, et al.: Immunology: hepatitis A virus link to atopic disease. Nature 2003, 425:576.The first association of polymorphisms in a virus receptor with atopic disease.PubMedCrossRefGoogle Scholar
  17. 17.
    McIntire JJ, Umetsu DT, DeKruyff RH: TIM-1, a novel allergy and asthma susceptibility gene. Springer Semin Immunopathol 2004, 25:335–348.PubMedCrossRefGoogle Scholar
  18. 18.
    Godfrey RC: Asthma and IgE levels in rural and urban communities of The Gambia. Clin Allergy 1975, 5:201–207.PubMedCrossRefGoogle Scholar
  19. 19.
    Yazdanbakhsh M, Kremsner PG, van Ree R: Allergy, parasites, and the hygiene hypothesis. Science 2002, 296:490–494.PubMedCrossRefGoogle Scholar
  20. 20.
    Lynch NR, Hagel I, Perez M, et al.: Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum. J Allergy Clin Immunol 1993, 92:404–411.PubMedCrossRefGoogle Scholar
  21. 21.
    King CL, Medhat A, Malhotra I, et al.: Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J Immunol 1996, 156:4715–4721.PubMedGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Braun-Fahrlander C, Riedler J, Herz U, et al.: Environmental exposure to endotoxin and its relation to asthma in schoolage children. N Engl J Med 2002, 347:869–877.PubMedCrossRefGoogle Scholar
  24. 24.
    McGuirk P, Mills KH: Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol 2002, 23:450–455.PubMedCrossRefGoogle Scholar
  25. 25.
    McMenamin C, Pimm C, McKersey M, Holt PG: Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells. Science 1994, 265:1869–1871.PubMedCrossRefGoogle Scholar
  26. 26.
    Seymour BW, Gershwin LJ, Coffman RL: Aerosol-induced immunoglobulin (Ig)-E unresponsiveness to ovalbumin does not require CD8+ or T cell receptor (TCR)-gamma/ delta+ T cells or interferon (IFN)-gamma in a murine model of allergen sensitization. J Exp Med 1998, 187:721–731.PubMedCrossRefGoogle Scholar
  27. 27.
    Akbari O, DeKruyff RH, Umetsu DT: Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001, 2:725–731.PubMedCrossRefGoogle Scholar
  28. 28.
    Gershon RK, Kondo K: Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 1970, 18:723–737.PubMedGoogle Scholar
  29. 29.
    Nishizuka Y, Sakakura T: Thymus and reproduction: sexlinked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969, 166:753–755.PubMedCrossRefGoogle Scholar
  30. 30.
    Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T: Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 1985, 161:72–87.PubMedCrossRefGoogle Scholar
  31. 31.
    Sakaguchi S, Sakaguchi N, Asano M, et al.: Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155:1151–1164.First identification of regulatory function in circulating CD25-expressing CD4+ T cells.PubMedGoogle Scholar
  32. 32.
    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.First identification of IL-10-producing CD4+ T regulatory cells.PubMedCrossRefGoogle Scholar
  33. 33.
    Das G, Augustine MM, Das J, et al.: An important regulatory role for CD4+CD8 alpha alpha T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc Natl Acad Sci U S A 2003, 100:5324–5329.PubMedCrossRefGoogle Scholar
  34. 34.
    Higgins SC, Lavelle EC, McCann C, et al.: Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J Immunol 2003, 171:3119–3127.PubMedGoogle Scholar
  35. 35.
    Cong Y, Weaver CT, Lazenby A, Elson CO: Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol 2002, 169:6112–6119.PubMedGoogle Scholar
  36. 36.
    Chen W, Jin W, Hardegen N, et al.: Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003, 198:1875–1886.PubMedCrossRefGoogle Scholar
  37. 37.
    Nishimura E, Sakihama T, Setoguchi R, et al.: Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells. Int Immunol 2004, 16:1189–1201.PubMedCrossRefGoogle Scholar
  38. 38.
    Powell BR, Buist NR, Stenzel P: An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr 1982, 100:731–737.PubMedCrossRefGoogle Scholar
  39. 39.
    Brunkow ME, Jeffery EW, Hjerrild KA, et al.: Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001, 27:68–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Chatila TA, Blaeser F, Ho N, et al.: JM2, encoding a fork headrelated protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 2000, 106:R75-R81.PubMedGoogle Scholar
  41. 41.
    Bennett CL, Christie J, Ramsdell F, et al.: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001, 27:20–21.PubMedCrossRefGoogle Scholar
  42. 42.
    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.First studies demonstrating an association between the IPEX syndrome in humans with mutations in the Foxp3 gene.PubMedCrossRefGoogle Scholar
  43. 43.
    Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057–1061.The first demonstration of a role for FOXP3 in the development of CD4+CD25+ T regulatory cells.PubMedCrossRefGoogle Scholar
  44. 44.
    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
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    O’Garra A, Vieira P: Regulatory T cells and mechanisms of immune system control. Nat Med 2004, 10:801–805.PubMedCrossRefGoogle Scholar
  47. 47.
    McMenamin C, Pimm C, McKersey M, Holt PG: Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells. Science 1994, 265:1869–1871.First description of the establishment of tolerance in the respiratory tract by repeated exposure to inhaled antigen.PubMedCrossRefGoogle Scholar
  48. 48.
    Hoyne GF, Askonas BA, Hetzel C, et al.: Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4+ T cells precedes the development of tolerance in vivo. Int Immunol 1996, 8:335–342.PubMedCrossRefGoogle Scholar
  49. 49.
    Hansen G, McIntire JJ, Yeung VP, et al.: CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergeninduced airway hyperreactivity and inflammation. J Clin Invest 2000, 105:61–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen Y, Kuchroo VK, Inobe J, et al.: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994, 265:1237–1240.PubMedCrossRefGoogle Scholar
  51. 51.
    Zuany-Amorim C, Sawicka E, Manlius C, et al.: Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T cells. Nature Med 2002, 8:625–629.PubMedCrossRefGoogle Scholar
  52. 52.
    Fantini MC, Becker C, Monteleone G, et al.: Cutting edge: TGFbeta 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
  53. 53.
    Nakao A, Miike S, Hatano M, et al.: Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med 2000, 192:151–158.PubMedCrossRefGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    Hoyne GF, Le Roux I, Corsin-Jimenez M, et al.: Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells. Int Immunol 2000, 12:177–185.First demonstration of the ability of Notch-Notch ligand interactions to induce tolerance to allergens.PubMedCrossRefGoogle Scholar
  57. 57.
    Ostroukhova M, Seguin-Devaux C, Oriss TB, et al.: Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 2004, 114:28–38.First description of a role for FOXP3- and cell surface TGF-β-expressing CD4+CD25+ T cells in peripheral tolerance in an in vivo antigen-driven disease model.PubMedCrossRefGoogle Scholar
  58. 58.
    Gorham JD, Guler ML, Fenoglio D, et al.: Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells. J Immunol 1998, 161:1664–1670.PubMedGoogle Scholar
  59. 59.
    Gorelik L, Constant S, Flavell RA: Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 2002, 195:1499–1505.PubMedCrossRefGoogle Scholar
  60. 60.
    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
  61. 61.
    Gorelik L, Fields PE, Flavell RA: Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression [In process citation]. J Immunol 2000, 165:4773–4777.PubMedGoogle Scholar
  62. 62.
    Chen CH, Seguin-Devaux C, Burke NA, et al.: Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med 2003, 197:1689–1699.First demonstration of a common mechanism by which soluble TGF-β blocks both Th1 and Th2 differentiation.PubMedCrossRefGoogle Scholar
  63. 63.
    Nakamura K, Kitani A, Strober W: Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001, 194:629–644.st study implicating membrane-bound TGF-β and contactdependent echanisms in suppressive functions of CD4+ T cellsPubMedCrossRefGoogle Scholar
  64. 64.
    Piccirillo CA, Letterio JJ, Thornton AM, et al.: CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 2002, 196:237–246.PubMedCrossRefGoogle Scholar
  65. 65.
    Wehrle-Haller B, Weston JA: Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development 1995, 121:731–742.PubMedGoogle Scholar
  66. 66.
    Sacca R, Cuff CA, Lesslauer W, Ruddle NH: Differential activities of secreted lymphotoxin-alpha3 and membrane lymphotoxin-alpha1beta2 in lymphotoxin-induced inflammation: critical role of TNF receptor 1 signaling. J Immunol 1998, 160:485–491.PubMedGoogle Scholar
  67. 67.
    Walker MR, Kasprowicz DJ, Gersuk VH, et al.: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25-T cells. J Clin Invest 2003, 112:1437–1443.PubMedCrossRefGoogle Scholar
  68. 68.
    Schramm C, Huber S, Protschka M, et al.: TGF(beta) regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo. Int Immunol 2004, 16:1241–1249.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    Zheng SG, Wang JH, Gray JD, et al.: Natural and induced CD4+CD25+ cells educate CD4+CD25-cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 2004, 172:5213–5221.PubMedGoogle Scholar
  71. 71.
    Cobbold SP, Castejon R, Adams E, et al.: Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 2004, 172:6003–6010.PubMedGoogle Scholar
  72. 72.
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA: Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004, 199:971–979.PubMedCrossRefGoogle Scholar
  73. 73.
    Ehrenstein MR, Evans JG, Singh A, et al.: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF-alpha therapy. J Exp Med 2004, 200:277–285.First sets of studies showing functional but not developmental impairment of CD4+CD25+ T regulatory cells in human disease.PubMedCrossRefGoogle Scholar
  74. 74.
    Karlsson MR, Rugtveit J, Brandtzaeg P: Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med 2004, 199:1679–1688.First study showing an association between T regulatory cell development and resolution of allergic symptoms in humans.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Marina Ostroukhova
    • 1
  • Anuradha Ray
    • 1
  1. 1.Department of Medicine, Pulmonary, Allergy and Critical Care MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA

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