Skip to main content
Download PDF

Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis

Autoimmunity Highlights volume 1, pages 45–51 (2010)Cite this article

Abstract

Regulatory T cells (Treg) are a CD4+ lymphocyte subset involved in self-tolerance and autoimmunity prevention. There is evidence for a phenotypic and/or functional impairment of this cell subset during the natural history of several chronic autoimmune/inflammatory diseases, including rheumatoid arthritis (RA). Although the intracellular transcription factor FoxP3 is thought to be the master regulator of Treg cell function, a number of other molecules expressed on the cell surface have been proposed for the identification of Treg cells. This is important in order to favour their possible selective isolation and in the development of new therapeutic strategies. In the present paper, available data on phenotypic and functional characterization of Treg cells in both peripheral blood and synovial fluid from RA patients are reviewed and their possible pathogenic role in triggering and perpetuating rheumatoid joint inflammation is discussed.

References

  1. Vandenbark AA, Offner H (2008) Critical evaluation of regulatory T cells in autoimmunity: are the most potent regulatory specificities being ignored? Immunology 125:1–13

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Dieckmann D, Bruett CH, Ploettner H et al (2002) Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196:247–253

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Lan RY, Ansari AA, Lian ZX et al (2005) Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 4:351–363

    Article  PubMed  CAS  Google Scholar 

  4. Sakaguchi S, Sakaguchi N, Asano M et al (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α chain (CD25), breakdown of a single mechanism of self tolerance causes various autoimmune disease. J Immunol 155:1151–1164

    PubMed  CAS  Google Scholar 

  5. Dieckmann D, Plottner H, Berchtold S et al (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Berthelot JM, Maugars Y (2004) Role of suppressor T cells in the pathogenesis of autoimmune diseases (including rheumatoid arthritis). Facts and hypotheses. Joint Bone Spine 71:374–380

    Article  PubMed  Google Scholar 

  7. Sakaguchi S, Wing K, Yamaguchi T (2009) Dynamics of peripheral tolerance and immune regulation mediated by Treg. Eur J Immunol 39:2331–2336

    Article  PubMed  CAS  Google Scholar 

  8. Bluestone JA, Abbas AK (2003) Natural versus adaptative regulatory T cells. Nat Rev Immunol 3:253–257

    Article  PubMed  CAS  Google Scholar 

  9. Shevach EM (2009) Mechanisms of foxP3+ T regulatory cell-mediated suppression. Immunity 30:636–645

    Article  PubMed  CAS  Google Scholar 

  10. Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptative foxP3+ regulatory T cells: more of the same or a division of labor? Immunity 30:626–635

    Article  PubMed  CAS  Google Scholar 

  11. Nocentini G, Giunchi L, Ronchetti S et al (1997) A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci U S A 94:6216–6221

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Klein S, Kretz CC, Krammer PH et al (2010) CD127(low/-) and FoxP3+ expression levels characterize different regulatory T cell populations in human peripheral blood. J Invest Dermatol 130:492–499

    Article  PubMed  CAS  Google Scholar 

  13. Chatila TA, Blaeser F, Ho N et al (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106:R75–R81

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Gambineri E, Torgerson TR, Ochs HD (2003) Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheum 15:430–435

    Article  CAS  Google Scholar 

  15. Fontenot JD, Gavin MA, Rudensky AY (2003) FoxP3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  PubMed  CAS  Google Scholar 

  16. Feuerer M, Hill JA, Mathis D et al (2009) FoxP3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 10:689–695

    Article  PubMed  CAS  Google Scholar 

  17. Aerts NE, Dombrecht EJ, Ebo DJ et al (2008) Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis. Cell Immunol 251:109–115

    Article  PubMed  CAS  Google Scholar 

  18. Gerli R, Nocentini G, Alunno A et al (2009) Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun Rev 8:426–430

    Article  PubMed  CAS  Google Scholar 

  19. Zhang B, Zhang X, Tang FL et al (2008) Clinical significance of increased CD4+CD25+FoxP3+ T cells in patients with new-onset systemic lupus erythematosus. Ann Rheum Dis 67:1037–1040

    Article  PubMed  CAS  Google Scholar 

  20. Miyara M, Amoura Z, Parizot C et al (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175:392–400

    Article  Google Scholar 

  21. Gottenberg JE, Lavie F, Abbed K et al (2005) CD4+CD25high regulatory T cells are not impaired in patients with primary Sjögren’s syndrome. J Autoimmun 24:235–242

    Article  PubMed  CAS  Google Scholar 

  22. Valencia X, Yarboro C, Illei G et al (2007) Deficient CD4+CD25high regulatory T cell function in patients with active systemic lupus erythematosus. J Immunol 178:2579–2588

    Article  PubMed  CAS  Google Scholar 

  23. Mellor-Pita S, Citores MJ, Castejon R et al (2006) Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis 65:553–554

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Barath S, Aleksza M, Tarr T et al (2007) Measurement of natural (CD4+CD25high) and inducible (CD4+IL-10+) regulatory T cells in patients with systemic lupus erythematosus. Lupus 16:489–496

    Article  PubMed  CAS  Google Scholar 

  25. Crispin JC, Martinez A, Alcocer-Varela J (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273–276

    Article  PubMed  Google Scholar 

  26. Liu MF, Wang CR, Fung LL et al (2004) Decreased CD4+CD25+T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 59:198–202

    Article  PubMed  Google Scholar 

  27. Kelchtermans H, De Klerck B, Mitera T et al (2005) Defective CD4+CD25+ regulatory T cell functioning in collagen induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-gamma. Arthritis Res Ther 7:R402–R415

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Morgan ME, Sutmuller RP, Witteveen HJ et al (2003) CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum 48:1452–1460

    Article  PubMed  Google Scholar 

  29. Morgan ME, Flierman R, van Duivenvoorde LM et al (2005) Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52:2212–2221

    Article  PubMed  CAS  Google Scholar 

  30. Cuzzocrea S, Ayroldi E, Di Paola R et al (2005) Role of glucocorticoid-induced TNF receptor family gene (GITR) in collageninduced arthritis. FASEB J 19:1253–1265

    Article  PubMed  CAS  Google Scholar 

  31. Toh ML, Miossec P (2007) The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheum 19:284–288

    Article  Google Scholar 

  32. van Roon JA, Bijlsma JW, Lafeber FP (2006) Diversity of regulatory T cells to control arthritis. Best Pract Res Clin Rheum 20:897–913

    Article  Google Scholar 

  33. Cao D, Malmstrom V, Baecher-Allan C et al (2003) Isolation and functional characterization of regulatory CD25brightCD4+ T cells from target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215–223

    Article  PubMed  CAS  Google Scholar 

  34. Van Amelsfort JM, Jacobs KM, Bijlsma JW et al (2004) CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype and function between peripheral blood and synovial fluid. Arthritis Rheum 50:2275–2285

    Google Scholar 

  35. Mottonen M, Heikkinen J, Mustonen L et al (2005) CD4+CD25+ T cells with phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 140:360–367

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Liu MF, Wang CR, Fung LL et al (2005) The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol 62:312–317

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Behrens F, Himsel A, Rehart S et al (2007) Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis. Ann Rheum Dis 66:1151–1156

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. van Amelsfort JM, van Roon JA, Noordegraaf M et al (2007) Proinflammatory mediator-induced reversal of CD4+CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum 56:732–742

    Article  PubMed  Google Scholar 

  40. Jiao Z, Wang W, Li J et al (2007) Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand J Rheumatol 36:428–433

    Article  PubMed  CAS  Google Scholar 

  41. Lin SC, Chen KH, Lin CH et al (2007) The quantitative analysis of peripheral blood FoxP3-expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Invest 37:987–996

    Article  PubMed  CAS  Google Scholar 

  42. Lawson CA, Brown AK, Bejarano V et al (2006) Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology 45:1210–1217

    Article  PubMed  CAS  Google Scholar 

  43. Flores-Borja F, Jury EC, Mauri C et al (2008) Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci U S A 105:19395–19400

    Article  Google Scholar 

  44. Venigalla RK, Tretter T, Krienke S et al (2008) Reduced CD4+CD25-T cell sensitivity to the suppressive function of CD4+CD25highCD127-/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum 58:2120–2130

    Article  PubMed  Google Scholar 

  45. Lim HW, Broxmeyer HE, Kim CH (2006) Regulation of trafficking receptor expression in human forkhead box P3+ regulatory T cells. J Immunol 177:840–851

    Article  PubMed  CAS  Google Scholar 

  46. Karagiannidis C, Akdis M, Holopainen P et al (2004) Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114:1425–1433

    Article  PubMed  CAS  Google Scholar 

  47. Raghavan S, Cao D, Widhe M et al (2009) FoxP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthritis and intra-articular corticosteroid treatment. Ann Rheum Dis 68:1908–1915

    Article  PubMed  CAS  Google Scholar 

  48. Ehrenstein MR, Evans JG, Singh A et al (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF therapy. J Exp Med 200:277–285

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Nadkarni S, Mauri C, Ehrenstein MR (2007) Anti-TNFα therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGFβ. J Exp Med 204:33–39

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Toubi E, Kessel A, Mahmoudov Z et al (2005) Increased spontaneous apoptosis of CD4+CD25+ T cells in patients with active rheumatoid arthritis is reduced by infliximab. Ann N Y Acad Sci 1051:506–514

    Article  PubMed  CAS  Google Scholar 

  51. Vigna-Perez M, Abud-Mendoza C, Alvarado Sanchez B et al (2005) Immune effects of therapy with adalimumab in patients with rheumatoid arthritis. Clin Exp Immunol 141:372–380

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Valencia X, Stephens J, Goldbach-Mansky R et al (2006) TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 106:253–261

    Article  Google Scholar 

  53. Dombrecht EJ, Aerts NE, Schuerwegh AJ et al (2006) Influence of anti-tumor necrosis factor therapy (Adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin Exp Rheumatol 24:31–37

    PubMed  CAS  Google Scholar 

  54. Yoshida H, Hashizume M, Suzuki M et al (2010) Anti-IL-6 receptor antibody suppressed T cell activation by inhibiting IL-2 production and inducing regulatory T cells. Eur J Pharmacol (in press)

Download references

Author information

Authors and Affiliations

  1. Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Perugia, via E. dal Pozzo, Perugia, I-06122, Italy

    Alessia Alunno, Elena Bartoloni, Onelia Bistoni & Roberto Gerli

  2. Section of Pharmacology, Toxicology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Perugia, I-06122, Perugia, Italy

    Giuseppe Nocentini, Simona Ronchetti, Maria Grazia Petrillo & Carlo Riccardi

Authors
  1. Alessia Alunno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Bartoloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Nocentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Onelia Bistoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simona Ronchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Grazia Petrillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlo Riccardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roberto Gerli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Gerli.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Alunno, A., Bartoloni, E., Nocentini, G. et al. Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis. Autoimmun Highlights 1, 45–51 (2010). https://doi.org/10.1007/s13317-010-0008-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13317-010-0008-2

Keywords

  • Treg cells
  • Rheumatoid arthritis
  • FoxP3 GITR

Autoimmunity Highlights

ISSN: 2038-3274

Contact us