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The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma

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Abstract

The role of distinct CD4+ T-cell populations in regulating the nature and strength of immune responses is well documented and in the past has principally focused on the cross-regulation of T-helper type 1 (Th1) and Th2 cells, which secrete interferon-γ and interleukin-4, respectively. However, the identification of T cells capable of suppressing responses mediated by Th1 and Th2 cells, termed regulatory T cells (Treg cells), has prompted a paradigm shift in our understanding of the regulation of immune responses to infection and environmental antigens. This article focuses on the role of Treg cells in the lungs following infection with respiratory pathogens and discusses the targeting of Treg cells in the development of new therapies for immune-mediated respiratory diseases, such as allergy and asthma.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gershon RK, Kondo K: Infectious immunological tolerance. Immunology 1971, 21:903–914.

    CAS  PubMed  Google Scholar 

  2. Sakaguchi S: Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000, 101:455–458.

    Article  CAS  PubMed  Google Scholar 

  3. Sakaguchi S, Sakaguchi N, Asano M, et al.: Immunologic self-tolerance 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.

    CAS  PubMed  Google Scholar 

  4. Shevach EM: CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002, 2:389–400.

    CAS  PubMed  Google Scholar 

  5. Kriegel MA, Lohmann T, Gabler C, et al.: Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med 2004, 199:1285–1291.

    Article  CAS  PubMed  Google Scholar 

  6. Ramsdell F: FoxP3 and natural regulatory T cells: key to a cell lineage? Immunity 2003, 19:165–168.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Mucida D, Pino-Lagos K, Kim G, et al.: Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. Immunity 2009, 30:471–472; author reply 472–473.

    Article  CAS  PubMed  Google Scholar 

  9. Lehmann J, Huehn J, de la Rosa M, et al.: Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25− regulatory T cells. Proc Natl Acad Sci U S A 2002, 99:13031–13036.

    Article  CAS  PubMed  Google Scholar 

  10. Sather BD, Treuting P, Perdue N, et al.: Altering the distribution of FoxP3(+) regulatory T cells results in tissue-specific inflammatory disease. J Exp Med 2007, 204:1335–1347.

    Article  CAS  PubMed  Google Scholar 

  11. Koch MA, Tucker-Heard G, Perdue NR, et al.: The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009, 10:595–602.

    Article  CAS  PubMed  Google Scholar 

  12. Zheng Y, Chaudhry A, Kas A, et al.: Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009, 458:351–356.

    Article  CAS  PubMed  Google Scholar 

  13. Fletcher JM, Lonergan R, Costelloe L, et al.: CD39+ FoxP3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009, 183:7602–7610.

    Article  CAS  PubMed  Google Scholar 

  14. Takahashi T, Kuniyasu Y, Toda M, et al.: Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 1998, 10:1969–1980.

    Article  CAS  PubMed  Google Scholar 

  15. Thornton AM, Shevach EM: Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 2000, 164:183–190.

    CAS  PubMed  Google Scholar 

  16. Garin MI, Chu CC, Golshayan D, et al.: Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 2007, 109:2058–2065.

    Article  CAS  PubMed  Google Scholar 

  17. Shalev I, Liu H, Koscik C, et al.: Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. J Immunol 2008, 180:249–260.

    CAS  PubMed  Google Scholar 

  18. 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 U S A 2008, 105:10113–10118.

    Article  CAS  PubMed  Google Scholar 

  19. Wing K, Onishi Y, Prieto-Martin P, et al.: CTLA-4 control over FoxP3+ regulatory T cell function. Science 2008, 322:271–275.

    Article  CAS  PubMed  Google Scholar 

  20. Liang B, Workman C, Lee J, et al.: Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 2008, 180:5916–5926.

    CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Exp Med 2002, 195:603–616.

    Article  CAS  PubMed  Google Scholar 

  23. McGuirk P, Johnson PA, Ryan EJ, Mills KH: Filamentous hemagglutinin and pertussis toxin from Bordetella pertussis modulate immune responses to unrelated antigens. J Infect Dis 2000, 182:1286–1289.

    Article  CAS  PubMed  Google Scholar 

  24. Chen C, Lee WH, Yun P, et al.: Induction of autoantigen-specific Th2 and Tr1 regulatory T cells and modulation of autoimmune diabetes. J Immunol 2003, 171:733–744.

    CAS  PubMed  Google Scholar 

  25. Chen W, Wahl SM: TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 2003, 14:85–89.

    Article  CAS  PubMed  Google Scholar 

  26. •• Zhou L, Chong MM, Littman DR: Plasticity of CD4+ T cell lineage differentiation. Immunity 2009, 30:646–655. This is a key review describing the plasticity of T-cell lineages.

    Article  CAS  PubMed  Google Scholar 

  27. Das J, Ren G, Zhang L, et al.: Transforming growth factor {beta} is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 2009, 206:2407–2416.

    Article  CAS  PubMed  Google Scholar 

  28. Osorio F, LeibundGut-Landmann S, Lochner M, et al.: DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol 2008, 38:3274–3281.

    Article  CAS  PubMed  Google Scholar 

  29. Yang XO, Nurieva R, Martinez GJ, et al.: Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008, 29:44–56.

    Article  CAS  PubMed  Google Scholar 

  30. Zheng SG, Wang J, Horwitz DA: Cutting edge: FoxP3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol 2008, 180:7112–7116.

    CAS  PubMed  Google Scholar 

  31. •• Veldhoen M, Uyttenhove C, van Snick J, et al.: Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 2008, 9:1341–1346. The identification of a novel population of CD4 + T cells that secrete IL-9, termed Th9 cells, may prove to be very important in the pathogenesis of allergic disorders.

    Article  CAS  PubMed  Google Scholar 

  32. Lu LF, Lind EF, Gondek DC, et al.: Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 2006, 442:997–1002.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Fukaura H, Kent SC, Pietrusewicz MJ, et al.: Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 1996, 98:70–77.

    Article  CAS  PubMed  Google Scholar 

  35. Weiner HL: Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001, 182:207–214.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. de Jong EC, Vieira PL, Kalinski P, et al.: Microbial compounds selectively induce Th1 cell-promoting or Th2 cell-promoting dendritic cells in vitro with diverse th cell-polarizing signals. J Immunol 2002, 168:1704–1709.

    PubMed  Google Scholar 

  38. Grohmann U, Orabona C, Fallarino F, et al.: CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002, 3:1097–1101.

    Article  CAS  PubMed  Google Scholar 

  39. Hemmi H, Takeuchi O, Kawai T, et al.: A Toll-like receptor recognizes bacterial DNA. Nature 2000, 408:740–745.

    Article  CAS  PubMed  Google Scholar 

  40. Moser M, Murphy KM: Dendritic cell regulation of Th1-Th2 development. Nat Immunol 2000, 1:199–205.

    Article  CAS  PubMed  Google Scholar 

  41. Gagliardi MC, Sallusto F, Marinaro M, et al.: Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming. Eur J Immunol 2000, 30:2394–2403.

    Article  CAS  PubMed  Google Scholar 

  42. d’Ostiani CF, Del Sero G, Bacci A, et al.: Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J Exp Med 2000, 191:1661–1674.

    Article  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. Ross PJ, Lavelle EC, Mills KHG, Boyd AP: Adenylate cyclase toxin from Bordetella pertussis synergises with lipopolysaccharide to promote innate IL-10 production and enhance the induction of Th2 and regulatory T cells. Infect Immunol 2003, 72:1568–1579.

    Article  CAS  Google Scholar 

  45. Lavelle EC, McNeela E, Armstrong ME, et al.: Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation. J Immunol 2003, 171:2384–2392.

    CAS  PubMed  Google Scholar 

  46. Bloom BR, Small PM: The evolving relation between humans and Mycobacterium tuberculosis. N Engl J Med 1998, 338:677–678.

    Article  CAS  PubMed  Google Scholar 

  47. Tsicopoulos A, Hamid Q, Varney V, et al.: Preferential messenger RNA expression of Th1-type cells (IFN-gamma+, IL-2+) in classical delayed-type (tuberculin) hypersensitivity reactions in human skin. J Immunol 1992, 148:2058–2061.

    CAS  PubMed  Google Scholar 

  48. Boussiotis VA, Tsai EY, Yunis EJ, et al.: IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 2000, 105:1317–1325.

    Article  CAS  PubMed  Google Scholar 

  49. Turner J, Gonzalez-Juarrero M, Ellis DL, et al.: In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J Immunol 2002, 169:6343–6351.

    CAS  PubMed  Google Scholar 

  50. Zuany-Amorim C, Sawicka E, Manlius C, et al.: Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002, 8:625–629.

    Article  CAS  PubMed  Google Scholar 

  51. Chen X, Zhou B, Li M, et al.: CD4(+)CD25(+)FoxP3(+) regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin Immunol 2007, 123:50–59.

    Article  CAS  PubMed  Google Scholar 

  52. Mason CM, Porretta E, Zhang P, Nelson S: CD4+ CD25+ transforming growth factor-beta-producing T cells are present in the lung in murine tuberculosis and may regulate the host inflammatory response. Clin Exp Immunol 2007, 148:537–545.

    Article  CAS  PubMed  Google Scholar 

  53. Qin XJ, Shi HZ, Liang QL, et al.: CD4+CD25+ regulatory T lymphocytes in tuberculous pleural effusion. Chin Med J (Engl) 2008, 121:581–586.

    CAS  Google Scholar 

  54. Ribeiro-Rodrigues R, Resende Co T, Rojas R, et al.: A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol 2006, 144:25–34.

    Article  CAS  PubMed  Google Scholar 

  55. Mills KH, Barnard A, Watkins J, Redhead K: Cell-mediated immunity to Bordetella pertussis: role of Th1 cells in bacterial clearance in a murine respiratory infection model. Infect Immun 1993, 61:399–410.

    CAS  PubMed  Google Scholar 

  56. Ryan M, Murphy G, Gothefors L, et al.: Bordetella pertussis respiratory infection in children is associated with preferential activation of type 1 T helper cells. J Infect Dis 1997, 175:1246–1250.

    Article  CAS  PubMed  Google Scholar 

  57. McGuirk P, Mahon BP, Griffin F, Mills KH: Compartmentalization of T cell responses following respiratory infection with Bordetella pertussis: hyporesponsiveness of lung T cells is associated with modulated expression of the co-stimulatory molecule CD28. Eur J Immunol 1998, 28:153–163.

    Article  CAS  PubMed  Google Scholar 

  58. Hickey FB, Brereton CF, Mills KH: Adenylate cyclase toxin of Bordetella pertussis inhibits TLR-induced IRF-1 and IRF-8 activation and IL-12 production and enhances IL-10 through MAPK activation in dendritic cells. J Leukoc Biol 2008, 84:234–243.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    CAS  PubMed  Google Scholar 

  60. Hanano R, Kaufmann SH: Effect on parasite eradication of Pneumocystis carinii-specific antibodies produced in the presence or absence of CD4(+) alphabeta T lymphocytes. Eur J Immunol 1999, 29:2464–2475.

    Article  CAS  PubMed  Google Scholar 

  61. Roths JB, Sidman CL: Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice. J Clin Invest 1992, 90:673–678.

    Article  CAS  PubMed  Google Scholar 

  62. Hori S, Carvalho TL, Demengeot J: CD25+CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur J Immunol 2002, 32:1282–1291.

    Article  CAS  PubMed  Google Scholar 

  63. McKinley L, Logar AJ, McAllister F, et al.: Regulatory T cells dampen pulmonary inflammation and lung injury in an animal model of pneumocystis pneumonia. J Immunol 2006, 177:6215–6226.

    CAS  PubMed  Google Scholar 

  64. Gereke M, Jung S, Buer J, Bruder D: Alveolar type II epithelial cells present antigen to CD4(+) T cells and induce FoxP3(+) regulatory T cells. Am J Respir Crit Care Med 2009, 179:344–355.

    Article  PubMed  Google Scholar 

  65. Luo ZX, Liu EM, Deng B, et al.: [Role of FoxP3 expression and CD4+CD25+ regulatory T cells on the pathogenesis of childhood asthma]. Zhonghua Er Ke Za Zhi 2006, 44:267–271.

    PubMed  Google Scholar 

  66. Saito K, Torii M, Ma N, et al.: Differential regulatory function of resting and preactivated allergen-specific CD4+ CD25+ regulatory T cells in Th2-type airway inflammation. J Immunol 2008, 181:6889–6897.

    CAS  PubMed  Google Scholar 

  67. Li Q, Shen HH: Neonatal bacillus Calmette-Guerin vaccination inhibits de novo allergic inflammatory response in mice via alteration of CD4+CD25+ T-regulatory cells. Acta Pharmacol Sin 2009, 30:125–133.

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. • Radulovic S, Jacobson MR, Durham SR, Nouri-Aria KT: Grass pollen immunotherapy induces FoxP3-expressing CD4+ CD25+ cells in the nasal mucosa. J Allergy Clin Immunol 2008, 121:1467–1472. This article demonstrates the potential of immunotherapeutic approaches for allergies based on Treg induction.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  72. 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.

    Article  CAS  PubMed  Google Scholar 

  73. •• Wakashin H, Hirose K, Maezawa Y, et al.: IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am J Respir Crit Care Med 2008, 178:1023–1032. This article reports that Th17 cells may cooperate with Th2 cells to induce neutrophilic and eosinophilic airway inflammation.

    Article  CAS  PubMed  Google Scholar 

  74. Scrivener S, Yemaneberhan H, Zebenigus M, et al.: Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study. Lancet 2001, 358:1493–1499.

    Article  CAS  PubMed  Google Scholar 

  75. Wilson MS, Taylor MD, Balic A, et al.: Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 2005, 202:1199–1212.

    Article  CAS  PubMed  Google Scholar 

  76. van der Kleij D, Yazdanbakhsh M: Control of inflammatory diseases by pathogens: lipids and the immune system. Eur J Immunol 2003, 33:2953–2963.

    Article  PubMed  CAS  Google Scholar 

  77. Walsh KP, Brady MT, Finlay CM, et al.: Infection with a helminth parasite attenuates autoimmunity through TGF-beta-mediated suppression of Th17 and Th1 responses. J Immunol 2009, 183:1577–1586.

    Article  CAS  PubMed  Google Scholar 

  78. Stepek G, Auchie M, Tate R, et al.: Expression of the filarial nematode phosphorylcholine-containing glycoprotein, ES62, is stage specific. Parasitology 2002, 125:155–164.

    Article  CAS  PubMed  Google Scholar 

  79. Braat H, McGuirk P, Ten Kate FJ, et al.: Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule. Gut 2007, 56:351–357.

    Article  CAS  PubMed  Google Scholar 

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Disclosure

Dr. McGuirk is an employee of Opsona Therapeutics.

Dr. Mills is a cofounder, a minority shareholder in, a consultant for, and a member of the scientific advisory board for Opsona Therapeutics.

Acknowledgments

This work was supported by Science Foundation Ireland.

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  1. Peter McGuirk

    Present address: Opsona Therapeutics Ltd., Institute of Molecular Medicine, St. James’s Hospital, Dublin 8, Ireland

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  1. School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland

    Peter McGuirk, Sarah C. Higgins & Kingston H. G. Mills

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  1. Peter McGuirk
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McGuirk, P., Higgins, S.C. & Mills, K.H.G. The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma. Curr Allergy Asthma Rep 10, 21–28 (2010). https://doi.org/10.1007/s11882-009-0078-2

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