Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 146 No. 3132 (2016)

Regulatory T cells: balancing protection versus pathology

  • Nikolas Rakebrandt
  • Katharina Littringer
  • Nicole Joller
DOI
https://doi.org/10.4414/smw.2016.14343
Cite this as:
Swiss Med Wkly. 2016;146:w14343
Published
31.07.2016

Summary

Foxp3+ regulatory T cells (Tregs) maintain immune tolerance, prevent autoimmunity and modulate immune responses during infection and cancer. Recent studies have revealed considerable heterogeneity and plasticity within the Treg compartment, depending on the immunological context, which may result in Tregs losing their suppressive function in inflammatory environments. We review how dysfunctional Tregs contribute to disease pathogenesis in inflammatory conditions and how inappropriate regulatory responses may hamper protective immunity in the context of infection and cancer. We also discuss how Tregs might be targeted therapeutically to re-establish a proper balance between regulatory and effector responses in autoimmunity, infections, and cancer.

References

  1. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6.
  2. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanov, JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20.
  3. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.
  4. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007;7(11):875–88.
  5. Veiga-Parga T, Sehrawat S, Rouse BT. Role of regulatory T cells during virus infection. Immunol Rev. 2013;255(1):182–96.
  6. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127(4):759–67.
  7. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011;11(2):119–30.
  8. Hori S. Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells. Immunol Rev. 2014;259(1):159–72.
  9. Sawant DV, Vignali DA. Once a Treg, always a Treg? Immunol Rev. 2014;259(1):173–91.
  10. Maier LM, Lowe CE, Cooper J, Downes K, Anderson DE, Severson C, et al. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production. PLoS Genet. 2009;5(1):e1000322.
  11. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423(6939):506–11.
  12. Battaglia M, Roncarolo MG. Immune intervention with T regulatory cells: past lessons and future perspectives for type 1 diabetes. Semin Immunol. 2011;23(3):182–94.
  13. Ohl K, Tenbrock K. Regulatory T cells in systemic lupus erythematosus. Eur J Immunol. 2015;45(2):344–55.
  14. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004;200(3):277–85.
  15. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–11.
  16. Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–700.
  17. Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, et al. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology. 2008;123(1):79–89.
  18. 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(7):971–9.
  19. Sellebjerg F, Krakauer M, Khademi M, Olsson T, Sorensen PS. FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis. Clin Exp Immunol. 2012;170(2):149–55.
  20. Hong J, Li N, Zhang X, Zheng B, Zhang JZ. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci U S A. 2005;102(18):6449–54.
  21. Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med. 2011;17(6):673–5.
  22. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol. 2011;186(7):3918–26.
  23. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell, DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10(6):595–602.
  24. Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009;326(5955):986–91.
  25. Koch MA, Thomas KR, Perdue NR, Smigiel KS, Srivastava S, Campbell DJ. T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity. 2012;37(3):501–10.
  26. McPherson RC, Turner DG, Mair I, O’Connor RA, Anderton SM. T-bet Expression by Foxp3(+) T Regulatory Cells is Not Essential for Their Suppressive Function in CNS Autoimmune Disease or Colitis. Front Immunol. 2015;6:69.
  27. Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther. 2004;6(4):R335–46.
  28. Ruprecht CR, Gattorno M, Ferlito F, Gregorio A, Martini A, Lanzavecchia A, et al. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J Exp Med. 2005;201(11):1793–803.
  29. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood. 2006;108(1):253–61.
  30. Grinberg-Bleyer Y, Saadoun D, Baeyens A, Billiard F, Goldstein JD, Gregoire S, et al. Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J Clin Invest. 2010;120(12):4558–68.
  31. Afzali B, Mitchell PJ, Edozie FC, Povoleri GA, Dowson SE, Demandt L, et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Eur J Immunol. 2013;43(8):2043–54.
  32. Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood. 2009;113(18):4240–9.
  33. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood. 2008;112(6):2340–52.
  34. Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G, et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci U S A. 2009;106(21):8635–40.
  35. Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8.
  36. Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785–99.
  37. Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science. 2010;329(5999):1667–71.
  38. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010;463(7282):808–12.
  39. Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, et al. Self-antigen-Driven Activation Induces Instability of Regulatory T Cells during an Inflammatory Autoimmune Response. Immunity. 2013;39(5):949–62.
  40. Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012;36(2):262–75.
  41. Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-Hora M, Kodama T, et al. Pathogenic conversion of Foxp3(+) T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62–8.
  42. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009;10(9):1000–7.
  43. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.
  44. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441(7090):231–4.
  45. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179–89.
  46. Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(8):2499–503.
  47. Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol. 2015;15(5):283–94.
  48. Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189.
  49. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science. 2012;335(6071):936–41.
  50. Suvas S, Azkur AK, Kim BS, Kumaraguru U, Rouse BT. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol. 2004;172(7):4123–32.
  51. Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003;197(1):111–9.
  52. Robinson K, Kenefeck R, Pidgeon EL, Shakib S, Patel S, Polson RJ, et al. Helicobacter pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses. Gut. 2008;57(10):1375–85.
  53. Dittmer U, He H, Messer RJ, Schimmer S, Olbrich AR, Ohlen C, et al. Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity. 2004;20(3):293–303.
  54. Andersson J, Boasso A, Nilsson J, Zhang R, Shire NJ, Lindback S, et al. The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. J Immunol. 2005;174(6):3143–7.
  55. Hisaeda H, Maekawa Y, Iwakawa D, Okada H, Himeno K, Kishihara K, et al. Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med. 2004;10(1):29–30.
  56. Walther M, Tongren JE, Andrews L, Korbel D, King E, Fletcher H, et al. Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity. 2005;23(3):287–96.
  57. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486–99.
  58. Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, et al. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med. 2014;211(9):1905–18.
  59. Zelinskyy G, Dietze K, Sparwasser T, Dittmer U. Regulatory T cells suppress antiviral immune responses and increase viral loads during acute infection with a lymphotropic retrovirus. PLoS Pathog. 2009;5(8):e1000406.
  60. Schmitz, I, Schneider, C, Frohlich, A, Frebel, H, Christ, D, Leonard, WJ, et al. IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLoS Pathog, 2013. 9(5): p. e1003362.
  61. Betts RJ, Ho AW, Kemeny DM. Partial depletion of natural CD4(+)CD25(+) regulatory T cells with anti-CD25 antibody does not alter the course of acute influenza A virus infection. PLoS One. 2011;6(11):e27849.
  62. Brincks EL, Roberts AD, Cookenham T, Sell S, Kohlmeier JE, Blackman MA, et al. Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection. J Immunol. 2013;190(7):3438–46.
  63. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, et al. A Distinct Function of Regulatory T Cells in Tissue Protection. Cell. 2015;162(5):1078–89.
  64. Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013;155(6):1282–95.
  65. Kuswanto W, Burzyn D, Panduro M, Wang KK, Jang YC, Wagers AJ, et al. Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells. Immunity. 2016;44(2):355–67.
  66. Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013;171(1):36–45.
  67. Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113(2):293–301.
  68. Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM, Royal RE, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008;14(17):5610–8.
  69. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–90.
  70. Sim GC, Martin-Orozco N, Jin L, Yang Y, Wu S, Washington E, et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest. 2014;124(1):99–110.
  71. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 1999;59(13):3128–33.
  72. Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ, Jr., et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med. 2012;4(134):134ra62.
  73. Boyman O, Surh CD, Sprent J. Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin Biol Ther. 2006;6(12):1323–31.
  74. Letourneau S, van Leeuwen EM, Krieg C, Martin C, Pantaleo G, Sprent J, et al. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25. Proc Natl Acad Sci U S A. 2010;107(5):2171–6.
  75. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561–84.
  76. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23–34.
  77. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73(12):3591–603.
  78. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, et al. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest. 2015;125(5):2046–58.
  79. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The Immunoreceptor TIGIT Regulates Antitumor and Antiviral CD8(+) T Cell Effector Function. Cancer Cell. 2014;26(6):923–37.
  80. Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 2015;125(11):4053–62.