Regulatory T cells as a tool in modulation of immune system

Authors: J. Bodor;  K. Pavelcová;  R. Klubal
Authors‘ workplace: Česká genetická banka, spol. s r. o., Praha
Published in: Čes. Revmatol., 21, 2013, No. 4, p. 170-182.
Category: Rewiev


Regulatory T cells (Tregs) are CD4+ Fopx3+ T cells that suppress immune responses in a dominant manner in vivo. In the same time our efforts to understand tolerance mechanism mediated by Tregs at the cellular and molecular levels holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity. They have been also shown to be effective in suppressing alloimunity in models of graft-versus-host disease and organ transplantation. It is now time to dissect what is actual impact of Tregs in such a therapeutic context. Building on extensive research in Treg biology and preclinical testing of therapeutic efficacy, we are now at the point of evaluating safety and efficacy of Treg therapy in humans. This review focuses on developing therapy for autoimmune diseases using CD4+ Foxp3+ Tregs, with an emphasis on the studies with principal aim to maximize the benefits while overcoming the challenges and risks of Treg cell therapy.

Key words:
Tregs, conventional CD4+ T cells, autoimmunity, transplantation, mechanisms of Treg-mediated suppression


1. Ehrlich P. Collected papers of Paul Ehrlich – vol. 2. New York: Pergamon 1957.

2. Burnet FM. The Clonal Selection Theory of Acquired Immunity. Cambridge: Cambridge University Press 1959.

3. Ivanyi J. Milan Hasek and the discovery of immunological tolerance. Nat Rev Immunol 2003; 3: 591–597.

4. Nossal GJ. Clonal anergy of B cells: a flexible, reversible, and quantitative concept. J Exp Med 1996; 183: 1953–56.

5. Sakaguchi S, Wing K, Miyara M. Regulatory T cells – a brief history and perspective. Eur J Immunol 2007; (Suppl. 1) 37: S116–123.

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

7. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 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.

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

9. Singh B, Read S, Asseman C et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001; 182: 190–200.

10. Feng S. Long-term management of immunosuppression after pediatric liver transplantation: is minimization or withdrawal desirable or possible or both? Curr Opin Organ Transplant 2008; 13: 506–512.

11. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003; 3: 199–210.

12. Bluestone JA, Tang Q. Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells Proc Natl Acad Sci USA 01 2004; (Suppl 2): 14622–14626.

13. Waldmann H, Adams E, Fairchild P, Cobbold S. Regulation and privilege in transplantation tolerance. J Clin Immunol 2008; 28: 716–725.

14. Trzonkowski P, Bieniaszewska M, Juscinska J, Dobyszuk A, Krzystyniak A, Marek N, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol 2009; 133: 22–26.

15. Brunstein CG, Miller JS, Cao Q, McKen DH., Hippen KL, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 2010; 117: 1061–1070.

16. Di Ianni M, Falzetti F, Carrotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GvHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011; 117: 3921–3928.

17. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2001; 299: 1057–1061.

18. Khattri R., Cox T, Yasako S, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory T cells. Nat Immunol 2003; 4: 337–342.

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

20. Gambieri E, Torgerson T, Ochs H. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic immunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 2003; 15: 430–435.

21. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Med Genet 2002; 39: 537–545.

22. Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic tolerance. J Immunol 1999; 162: 5317–5326.

23. Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009; 30: 899–911.

24. Danke NA, Koelle DM, Yee C, et al Autoreactive T cells in healthy individuals. J Immunol 2004; 172: 5967–5972.

25. Wing K, Lindgren S, Kollberg G, et al. CD4 T cell activation by myelin oligodendrocyte glycoprotein is suppressed by adult but not cord blood CD25+ T cells. Eur J Immunol 2003; 33: 579–587.

26. Gnjatic S, Altorki NK, Tang DN, et al. NY-ESO-1 DNA vaccine induces T-cell responses that are suppressed by regulatory T cells. Clin Cancer Res 2009; 15: 2130–2139.

27. Danke NA, Yang J, Greenbaum C, Kwok WW. Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. J Autoimmun 2005; 25: 303-311.

28. Yang J, Danke N, Roti M, et al. CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope. J Autoimmun 2008; 31: 30–41.

29. Baxter AG. The origin and application of experimental autoimmune encephalomyelitis. Nat Rev Immunol 2007; 7: 904–912.

30. Scott DL, Wolfe F, Huizinga TW. Rheumatoid Arthritis. Lancet 2010; 376: 1094–1108.

31. Partlett R, Roussou E. The treatment of rheumatoid arthritis during pregnancy. Rheumatol Intl 2011; 31: 445–449.

32. de Man YA, Dolhain RJ, van de Geijn FE, et al. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum 2008; 59: 1241–1248.

33. Hench PS. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrosis, and intermittent hydrarthrosis. Mayo Clin Proc 1938; 13: 161–167.

34. Golding A, Hague UJ, Giles JT. Rheumatoid arthritis and reproduction. Rheum Dis Clin North Am 2007; 33: 319–343.

35. Kallikourdis M, Andersen KG, Welch KA, Betz AG. Alloantigen-enhanced accumulation of CCR5+ ‘effector’ regulatory T cells in the gravid uterus. Proc Natl Acad Sci USA 2007; 104: 594–599.

36. Kahn DA, Baltimore D. Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc Natl Acad Sci USA 2010; 107: 9299–9304.

37. Munoz-Suano A, Kallikourdis M, Sarris M, Betz AG. Regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun 2012; 38: 103–108.

38. Zaccone P, Fehérvári Z, Blanchard L, et al. Autoimmune thyroid disease induced by thyroglobulin and lipopolysaccharide is inhibited by soluble TNF receptor type I. Eur J Immunol 2002; 32: 1021–1028.

39. Eriksson U, Ricci R, Hunziker L, Kurrer MO, Oudit GY, Watts TH. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 2003; 9: 1484–1490.

40. Watanabe H, Inaba M, Adachi Y, Sugiura K, Hisha H, Iguchi T, et al. Experimental autoimmune thyroiditis induced by thyroglobulin-pulsed dendritic cells. Autoimmunity 1999; 31: 273–282.

41. Gehring AJ, Rojas RE, Canaday DH, et al. The mycobacterium tuberculosis 19-kilodalton lipoprotein inhibits gamma interferon-regulated HLA-DR and Fc gamma R1 on human macrophages through Toll-like receptor 2. Infect Immun 2003; 71: 4487–4497.

42. McGeachy MJ, Stephens LA, Anderton SM. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J Immunol 2005; 175: 3025–3032.

43. Kohm AP, Carpenter PA, Anger HA, Miller SD. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 2002; 169: 4712–4716.

44. Morris GP, Yan Y, David CS, Kong YM. H2A- and H2E-derived CD4+CD25+ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis. J Immunol 2005; 174: 3111–3116.

45. Reddy J, et al. Myelin proteolipid protein-specific CD4+CD25+ regulatory T cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2004; 101: 15434–15439.

46. Vaeth M, Gogishvili T, Bopp T, et al. Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1). Proc Natl Acad Sci USA 2011; 108: 2480–2485.

47. Bopp T, Becker C, Klein M, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007; 204: 1303–1310.

48. Bodor J, Bopp T, Vaeth M, et al. Cyclic AMP underpins suppression by regulatory T cells. Eur J Immunol 2012; 42: 1375–1384.

49. Becker C, Bopp T, Jonuleit H. Boosting regulatory T cell function by CD4 stimulation enters the clinic. Front Immunol 2012; 3: 1–9.

50. Shevach EM. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity 2009; 30: 636–645.

51. Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8: 523–532.

52. Tang Q, Bluestone J. The Foxp3+ regulatory T cell: jack of all trades, master of regulation. Nat Immunol 2008; 9: 239–244.

53. Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192: 303–310.

54. Read S, Malstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays and essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J Exp Med 2000; 192: 295–302.

55. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 2009; 206: 1717–1725.

56. Vendetti S, Riccomi A, Sacchi A, et al. Cyclic adenosine 5’-monophosphate and calcium induce CD152 (CTLA-4) up-regulation in resting CD4+ T lymphocytes. J Immunol 2002; 169: 6231–6235.

57. Bodor J, Fehervari Z, Diamond B, Sakaguchi S. ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells. Eur J Immunol 2007; 37: 884–895.

58. Lone AM, Tasken K. Proinflammatory and immunoregulatory roles of eicosanoids in T cells. Front Immunol 2013; 4: 1–15.

59. Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol 1953; 7: 320–338.

60. Erlebacher A, Vencato D, Price KA, et al. Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J Clin Invest 2007; 117: 1399–1411.

61. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 2012; 490: 102–106.

62. Bizargity P, Bonney EA. Dendritic cells, a family portrait at mid-gestation. Immunology 2009; 126: 565–578.

63. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531–564.

64. Josefowicz SZ, Niec RE, Kim HY, et al. Extrathymically generated regulatory T cells control mucosal Th2 inflammation. Nature 2012; 482: 395–399.

65. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nature Immunol 2004; 5: 266–271.

66. Zenclussen AC, Gerlof K, Zenclussen ML, et al. Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface. Eur J Immunol 2006; 36: 82–94.

67. Mjosberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory T cells and T helper 1, T helper 2 and T helper 17 cells in human early pregnancy decidua. Biol Reprod 2010; 82: 698–705.

68. Dimova T, Nagaeva O, Stenqvist AC, et al. Maternal Foxp3 expressing CD4+CD25+ and CD4+CD25- regulatory T cell populations are enriched in human early normal pregnancy decidua: a phenotypic study of paired decidual and peripheral blood samples. Am J Reprod Immunol 2011; 66 (Suppl. 1): 44–56.

69. Davies JD, O'Connor E, Hall D, et al. CD4+CD45RB low-density cells from untreated mice prevent acute allograft reaction. J Immunol 1999; 163: 5353–5357.

70. Taylor PA, Noelle RJ, Blazar BR. CD4+CD25+ immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med 2001; 193: 1311–1318.

71. Earle KE, Tang Q, Zhou X, et al. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clin Immunol 2005; 115: 3–9.

72. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4+CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med 2002; 196: 401–406.

73. Benghiat FS, Graca L, Braun MY, Detienne S, Moore F, Buonocore S, et al. Critical Influence of natural regulatory CD25+ T cells on the fate of allografts in the absence of immunosuppression. Transplantation 2005; 79: 648–654.

74. Bolton EM. Regulatory T cells in transplantation: natural or induced? Transplantation 2005; 79: 643–645.

75. Lin YJ, Hara H, Tai HC, et al. Suppressive efficacy and proliferative capacity of human regulatory T cells in allogeneic and xenogeneic responses. Transplantation 2008; 86: 1452–1462.

76. Wise MP, Bemelman F, Cobbold SP, Waldmann H. Linked suppression of skin graft rejection can operate through indirect recognition. J Immunol 1998; 161: 5813–5816.

77. Ochando JC, Homma C, Yang Y, et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 2006; 7: 652–662.

78. Verginis P, McLaughlin KA, Wucherpfennig KW, et al. Induction of antigen-specific regulatory T cells in wild type mice: visualization and targets of suppression. Proc Natl Acad Sci USA 2008; 105: 3479–3484.

79. Hara M, Kingsley CI, Niimi M, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 2001; 166: 3789–3796.

80. Yamada A, Chandraker A, Laufer TM, et al. Recipient MHC class II expression is required to achieve long-term survival of murine cardiac allografts after costimulatory blockade. J Immunol 2001; 167: 5522–5526.

81. Callaghan CJ, Rouhani FJ, Negus MC., et al. Abrogation of antibody-mediated allograft rejection by regulatory CD4 T cells with indirect allospecificity. J Immunol 2007; 178: 2221–2228.

82. Nadig SN, Wieckekiewicz J, Wu DC, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med 2010; 16: 809–813.

83. Brennan TV, Tang Q, Liu FC, et al. Requirements for prolongation of allograft survival with regulatory T cell infusion in lymphosufficient hosts. J Surg Res 2011; 169: e69–75.

84. Sagoo P, Ali N, Garg G, Nestle FO, et al. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med 2011; 3: 83ra42.

85. Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 2008; 14: 88–92.

86. Tsang JY, Tanriver Y, Jiang S, et al. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCRT gene transfer favors transplantation tolerance in mice. J Clin Invest 2008; 118: 3619–3628.

87. Trzonkowski P, Zilvetti M, Friend P, Wood KJ. Recipient memory-like lymphocytes remain unresponsive to graft antigens after CAMPATH-1H induction with reduced maintenance immunosuppression. Transplantation 2006; 82: 1342–1351.

88. Pearl JP, Parris J, Hale DA., et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 2005; 5: 465–474.

89. Bloom DD, Chang Z, Fechner JH, et al. CD4+CD25+FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with campath-1H. Am J Transplant 2008; 8: 793–802.

90. Lopez M, Clarkson MR, Albin M, et al. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol 2006; 17: 2844–2853.

91. Hester J, Schiopu A, Nadig SN, Wood KJ. Low dose of rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo. Am J Transplant 2012; 12: 2008–2016.

92. Shin HJ, Baker J, Leveson-Gower DB, et al Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. Blood 2011; 118: 2342–2350.

93. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365: 2055–2066.

Dermatology & STDs Paediatric rheumatology Rheumatology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account