Skip to main content

Advertisement

SpringerLink
Log in

Functional Defects of Treg Cells: New Targets in Rheumatic Diseases, Including Ankylosing Spondylitis

  • Spondyloarthritis (M Khan, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of review

This study aims to review the advances of Treg cell biology, the functional defects of Treg cells, and the potential strategies for the experimental, preclinical or clinical application of Treg cell therapy in the context of autoimmune/immune-mediated rheumatic diseases.

Recent findings

CD4+CD25+ regulatory T (Treg) cells are a phenotypically and functionally heterogeneous subset of lymphocytes that prevent a variety of autoimmune diseases. As in many autoimmune diseases, the functional defects of Treg cells are supposed to play relevant roles in the pathogenesis and development of systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, and other autoimmune/immune-mediated rheumatic diseases. Consequently, manipulation and modulation of Treg cells represent a potent strategy for therapeutic benefit in many such diseases.

Summary

A further understanding of the functional defects of Treg cells in rheumatic diseases will contribute to find new targets and therapies in rheumatic diseases, including ankylosing spondylitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  1. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.

    Article  CAS  PubMed  Google Scholar 

  2. 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(3):1151–64.

    CAS  PubMed  Google Scholar 

  3. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.

    Article  CAS  PubMed  Google Scholar 

  6. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol. 2012;12(3):157–67.

    Article  CAS  PubMed  Google Scholar 

  7. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  8. Prakken B, Ellen W, van Wijk F. Editorial: quality or quantity? Unraveling the role of Treg cells in rheumatoid arthritis. Arthritis Rheum. 2013;65(3):552–4.

    Article  PubMed  Google Scholar 

  9. Scheinecker C, Bonelli M, Smolen JS. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. J Autoimmun. 2010;35(3):269–75.

    Article  CAS  PubMed  Google Scholar 

  10. Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N. Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2016;22(7):2195–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. • Guo H, Zheng M, Zhang K, et al. Functional defects in CD4+ CD25high FoxP3+ regulatory cells in ankylosing spondylitis. Sci Rep. 2016;6:37559. This study shows that functional defects of Treg cells are present in AS patients, that may be caused by abnormal of IL-2 signaling and CNS2 methylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Haribhai D, Lin W, Edwards B, Ziegelbauer J, Salzman NH, Carlson MR, et al. A central role for induced regulatory T cells in tolerance induction in experimental colitis. J Immunol. 2009;182(6):3461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity. 2008;28(1):100–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004;4(9):665–74.

    Article  CAS  PubMed  Google Scholar 

  15. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006;108(5):1571–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science. 1995;268(5216):1472–6.

    Article  CAS  PubMed  Google Scholar 

  17. Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity. 2002;17(2):167–78.

    Article  CAS  PubMed  Google Scholar 

  18. Almeida AR, Legrand N, Papiernik M, Freitas AA. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol. 2002;169(9):4850–60.

    Article  PubMed  Google Scholar 

  19. Lourenco EV, La Cava A. Natural regulatory T cells in autoimmunity. Autoimmunity. 2011;44(1):33–42.

    Article  CAS  PubMed  Google Scholar 

  20. Roncarolo MG, Gregori S, Bacchetta R, Battaglia M. Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr Top Microbiol Immunol. 2014;380:39–68.

    CAS  PubMed  Google Scholar 

  21. Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol. 2007;37(1):129–38.

    Article  CAS  PubMed  Google Scholar 

  22. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5(2):e38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Polansky JK, Schreiber L, Thelemann C, Ludwig L, Krüger M, Baumgrass R, et al. Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med (Berl). 2010;88(10):1029–40.

    Article  CAS  Google Scholar 

  24. Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med. 2007;204(7):1543–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sojka DK, Huang YH, Fowell DJ. Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology. 2008;124(1):13–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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(29):10113–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5.

    Article  CAS  PubMed  Google Scholar 

  28. Sarris M, Andersen KG, Randow F, Mayr L, Betz AG. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity. 2008;28(3):402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci U S A. 2010;107(7):3058–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172(2):834–42.

    Article  CAS  PubMed  Google Scholar 

  31. Collison LW, Vignali DA. In vitro Treg suppression assays. Methods Mol Biol. 2011;707:21–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mirlekar B, Patil S, Bopanna R, Chattopadhyay S. MAR binding protein SMAR1 favors IL-10 mediated regulatory T cell function in acute colitis. Biochem Biophys Res Commun. 2015;464(2):647–53.

    Article  CAS  PubMed  Google Scholar 

  33. Joetham A, Takeda K, Taube C, et al. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J Immunol. 2007;178(3):1433–42.

    Article  CAS  PubMed  Google Scholar 

  34. 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(5):629–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A. 2003;100(19):10878–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9.

    Article  CAS  PubMed  Google Scholar 

  37. Bardel E, Larousserie F, Charlot-Rabiega P, Coulomb-L’Hermine A, Devergne O. Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL-35. J Immunol. 2008;181(10):6898–905.

    Article  CAS  PubMed  Google Scholar 

  38. Thiolat A, Denys A, Petit M, Biton J, Lemeiter D, Herve R, et al. Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. Cytokine. 2014;69(1):87–93.

    Article  CAS  PubMed  Google Scholar 

  39. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova 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.

    Article  CAS  PubMed  Google Scholar 

  40. Sanchez E, Rueda B, Orozco G, et al. Analysis of a GT microsatellite in the promoter of the foxp3/scurfin gene in autoimmune diseases. Hum Immunol. 2005;66(8):869–73.

    Article  CAS  PubMed  Google Scholar 

  41. Lin YC, Lee JH, Wu AS, et al. Association of single-nucleotide polymorphisms in FOXP3 gene with systemic lupus erythematosus susceptibility: a case-control study. Lupus. 2011;20(2):137–43.

    Article  CAS  PubMed  Google Scholar 

  42. Howson JM, Walker NM, Smyth DJ, Todd JA. Analysis of 19 genes for association with type I diabetes in the type I diabetes genetics consortium families. Genes Immun. 2009;10(Suppl 1):S74–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dal Ben ER, Do PC, Baptista TS, Bauer ME, Staub HL. Patients with systemic lupus erythematosus and secondary antiphospholipid syndrome have decreased numbers of circulating CD4(+)CD25(+)Foxp3(+) Treg and CD3(−)CD19(+) B cells. Rev Bras Reumatol. 2014;54(3):241–6.

    Article  PubMed  Google Scholar 

  44. Szmyrka-Kaczmarek M, Kosmaczewska A, Ciszak L, Szteblich A, Wiland P. Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus. Postepy Hig Med Dosw (Online). 2014;68:893–8.

    Article  Google Scholar 

  45. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol. 2005;175(12):8392–400.

    Article  CAS  PubMed  Google Scholar 

  46. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003;21(3):273–6.

    Article  PubMed  Google Scholar 

  47. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579–88.

    Article  CAS  PubMed  Google Scholar 

  48. Suarez A, Lopez P, Gomez J, Gutierrez C. Enrichment of CD4+ CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann Rheum Dis. 2006;65(11):1512–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bonelli M, Savitskaya A, von Dalwigk K, Steiner CW, Aletaha D, Smolen JS, et al. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int Immunol. 2008;20(7):861–8.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jiao Z, Wang W, Jia R, Li J, You H, Chen L, et al. Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand J Rheumatol. 2007;36(6):428–33.

    Article  CAS  PubMed  Google Scholar 

  52. Sempere-Ortells JM, Perez-Garcia V, Marin-Alberca G, et al. Quantification and phenotype of regulatory T cells in rheumatoid arthritis according to disease activity score-28. Autoimmunity. 2009;42(8):636–45.

    Article  CAS  PubMed  Google Scholar 

  53. Kawashiri SY, Kawakami A, Okada A, et al. CD4+CD25(high)CD127(low/−) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis. J Rheumatol. 2011;38(12):2517–21.

    Article  CAS  PubMed  Google Scholar 

  54. Niu Q, Cai B, Huang ZC, Shi YY, Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int. 2012;32(9):2731–6.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. Lina C, Conghua W, Nan L, Ping Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol. 2011;31(4):596–605.

    Article  PubMed  CAS  Google Scholar 

  57. Cao D, Malmstrom V, Baecher-Allan C, et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol. 2003;33(1):215–23.

    Article  CAS  PubMed  Google Scholar 

  58. Mottonen M, Heikkinen J, Mustonen L, Isomaki P, Luukkainen R, Lassila O. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol. 2005;140(2):360–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu MF, Wang CR, Fung LL, Lin LH, Tsai CN. The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol. 2005;62(3):312–7.

    Article  CAS  PubMed  Google Scholar 

  60. Dejaco C, Duftner C, Klauser A, Schirmer M. Altered T-cell subtypes in spondyloarthritis, rheumatoid arthritis and polymyalgia rheumatica. Rheumatol Int. 2010;30(3):297–303.

    Article  PubMed  Google Scholar 

  61. Lin SC, Chen KH, Lin CH, Kuo CC, Ling QD, Chan CH. The quantitative analysis of peripheral blood FOXP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Investig. 2007;37(12):987–96.

    Article  CAS  Google Scholar 

  62. Ji L, Geng Y, Zhou W, Zhang Z. A study on relationship among apoptosis rates, number of peripheral T cell subtypes and disease activity in rheumatoid arthritis. Int J Rheum Dis. 2016;19(2):167–71.

    Article  CAS  PubMed  Google Scholar 

  63. Dombrecht EJ, Aerts NE, Schuerwegh AJ, Hagendorens MM, Ebo DG, van Offel J, et al. Influence of anti-tumor necrosis factor therapy (adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin Exp Rheumatol. 2006;24(1):31–7.

    CAS  PubMed  Google Scholar 

  64. van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004;50(9):2775–85.

    Article  PubMed  Google Scholar 

  65. Han GM, O’Neil-Andersen NJ, Zurier RB, Lawrence DA. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol. 2008;253(1–2):92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. van Amelsfort JM, van Roon JA, Noordegraaf M, et al. Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum. 2007;56(3):732–42.

    Article  PubMed  CAS  Google Scholar 

  67. Cao D, Borjesson O, Larsson P, Rudin A, Gunnarsson I, Klareskog L, et al. FOXP3 identifies regulatory CD25bright CD4+ T cells in rheumatic joints. Scand J Immunol. 2006;63(6):444–52.

    Article  CAS  PubMed  Google Scholar 

  68. Moradi B, Schnatzer P, Hagmann S, Rosshirt N, Gotterbarm T, Kretzer J, et al. CD4(+)CD25(+)/highCD127low/(−) regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints—analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res Ther. 2014;16(2):R97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Rapetti L, Chavele KM, Evans CM, Ehrenstein MR. B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis. Ann Rheum Dis. 2015;74(1):294–302.

    Article  CAS  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2008;105(49):19396–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nadkarni S, Mauri C, Ehrenstein MR. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med. 2007;204(1):33–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bowness P. HLA-B27. Annu Rev Immunol. 2015;33:29–48.

    Article  CAS  PubMed  Google Scholar 

  74. Chen L, Ridley A, Hammitzsch A, al-Mossawi MH, Bunting H, Georgiadis D, et al. Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis. Ann Rheum Dis. 2016;75(5):916–23.

    Article  CAS  PubMed  Google Scholar 

  75. Walter GJ, Evans HG, Menon B, Gullick NJ, Kirkham BW, Cope AP, et al. Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127(low) regulatory T cells. Arthritis Rheum. 2013;65(3):627–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang C, Liao Q, Hu Y, Zhong D. T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis. Exp Ther Med. 2015;9(1):250–6.

    Article  CAS  PubMed  Google Scholar 

  77. Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum. 2008;58(8):2307–17.

    Article  PubMed  Google Scholar 

  78. Ye L, Goodall JC, Zhang L, Putintseva EV, Lam B, Jiang L, et al. TCR usage, gene expression and function of two distinct FOXP3(+)Treg subsets within CD4(+)CD25(hi) T cells identified by expression of CD39 and CD45RO. Immunol Cell Biol. 2016;94(3):293–305.

    Article  CAS  PubMed  Google Scholar 

  79. Wu Y, Ren M, Yang R, Liang X, Ma Y, Tang Y, et al. Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4+CCR6+ Th/Treg cell subset imbalance in ankylosing spondylitis. Arthritis Res Ther. 2011;13(1):R29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhao SS, Hu JW, Wang J, Lou XJ, Zhou LL. Inverse correlation between CD4+ CD25high CD127low/− regulatory T-cells and serum immunoglobulin A in patients with new-onset ankylosing spondylitis. J Int Med Res. 2011;39(5):1968–74.

    Article  CAS  PubMed  Google Scholar 

  81. Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010;33(3):301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105(12):4743–8.

    Article  CAS  PubMed  Google Scholar 

  83. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177(12):8338–47.

    Article  CAS  PubMed  Google Scholar 

  84. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Battaglia M, Stabilini A, Draghici E, Migliavacca B, Gregori S, Bonifacio E, et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes. 2006;55(6):1571–80.

    Article  CAS  PubMed  Google Scholar 

  86. Monti P, Scirpoli M, Maffi P, Piemonti L, Secchi A, Bonifacio E, et al. Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells. Diabetes. 2008;57(9):2341–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes. 2012;61(9):2340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Penaranda C, Tang Q, Bluestone JA. Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol. 2011;187(4):2015–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Belghith M, Bluestone JA, Barriot S, Mégret J, Bach JF, Chatenoud L. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med. 2003;9(9):1202–8.

    Article  CAS  PubMed  Google Scholar 

  90. Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A. 1994;91(1):123–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Goto R, You S, Zaitsu M, Chatenoud L, Wood KJ. Delayed anti-CD3 therapy results in depletion of alloreactive T cells and the dominance of Foxp3+ CD4+ graft infiltrating cells. Am J Transplant. 2013;13(7):1655–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692–8.

    Article  CAS  PubMed  Google Scholar 

  93. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352(25):2598–608.

    Article  CAS  PubMed  Google Scholar 

  94. Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Mannurita SC, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146(3):248–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liao W, Lin JX, Wang L, Li P, Leonard WJ. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol. 2011;12(6):551–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity. 2009;30(2):204–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yu A, Snowhite I, Vendrame F, Rosenzwajg M, Klatzmann D, Pugliese A, et al. Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms supports the use of low-dose IL-2 therapy in type 1 diabetes. Diabetes. 2015;64(6):2172–83.

    Article  CAS  PubMed  Google Scholar 

  98. • 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. This review summarized the recent studies on the therapeutic effects of low-dose interleukin-2 in autoimmune diseases and inflammation by specifically expanding and activating Treg cells.

    Article  CAS  PubMed  Google Scholar 

  99. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP III, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kennedy-Nasser AA, Ku S, Castillo-Caro P, Hazrat Y, Wu MF, Liu H, et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Cancer Res. 2014;20(8):2215–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22):2067–77.

    Article  CAS  PubMed  Google Scholar 

  102. Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013;1(4):295–305.

    Article  CAS  PubMed  Google Scholar 

  103. von Spee-Mayer C, Siegert E, Abdirama D, Rose A, Klaus A, Alexander T, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2016;75(7):1407–15.

    Article  CAS  Google Scholar 

  104. • He J, Zhang X, Wei Y, et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016;22(9):991–3. This study in SLE patients shows that low-dose IL-2 treatment selectively modulated the Treg cells and markedly decreased the disease activity.

    Article  CAS  PubMed  Google Scholar 

  105. Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2009;58(3):652–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. • Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189. This study reports on the successful isolation, expansion, and reinfusion of poly Treg cells in T1D patients, and there were no obviously adverse events and infusion reactions.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Tang Q, Bluestone JA. Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb Perspect Med 2013;3(11):a015552.

  108. Tang Q, Bluestone JA, Kang SM. CD4(+)Foxp3(+) regulatory T cell therapy in transplantation. J Mol Cell Biol. 2012;4(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  109. Hippen KL, Merkel SC, Schirm DK, Sieben CM, Sumstad D, Kadidlo DM, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med. 2011;3(83):83ra41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006;108(13):4260–7.

    Article  CAS  PubMed  Google Scholar 

  111. Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117(14):3921–8.

    Article  PubMed  CAS  Google Scholar 

  112. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117(3):1061–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Martelli MF, Di Ianni M, Ruggeri L, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124(4):638–44.

    Article  CAS  PubMed  Google Scholar 

  114. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, et al. Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817–20.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets—results of one year follow-up. Clin Immunol. 2014;153(1):23–30.

    Article  CAS  PubMed  Google Scholar 

  116. Brunstein CG, Miller JS, McKenna DH, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016;127(8):1044–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. • Rossetti M, Spreafico R, Saidin S, et al. Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region. J Immunol. 2015;194(1):113–24. This study in rheumatological settings demonstrated that the feasibility and effectiveness of the expansion protocol with Treg cells derived from RA patients, and Treg cell expansion with rapamycin as the protocol of choice for clinical application.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi’an, 710032, Shaanxi Province, People’s Republic of China

    Jinlin Miao & Ping Zhu

Authors
  1. Jinlin Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ping Zhu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Right and Informed Consent

This is a review article that does not report any new unpublished data involving human or animal subjects.

Additional information

This article is part of Topical Collection on Spondyloarthritis

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miao, J., Zhu, P. Functional Defects of Treg Cells: New Targets in Rheumatic Diseases, Including Ankylosing Spondylitis. Curr Rheumatol Rep 20, 30 (2018). https://doi.org/10.1007/s11926-018-0729-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-018-0729-1

Keywords

Search

Navigation