Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases

Nature Reviews Immunology volume 10, pages 849–859 (2010)Cite this article

Subjects

Key Points

  • There is evidence of impaired regulation by CD4+CD25+FOXP3+ regulatory T (TReg) cells in the human autoimmune diseases type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis.

  • Causes of this impaired tolerance include: inadequate numbers of TReg cells, TReg cell-intrinsic defects and factors extrinsic to TReg cells that allow escape from suppression, including the resistance of effector T cells to suppression and factors present in the inflammatory milieu, such as cytokines and antigen-presenting cells.

  • The approaches by which these mechanisms of failed tolerance can be pursued must take into account how best to 'count' TReg cells and how to carry out functional suppression assays using human samples.

  • Multiple studies that enumerate TReg cells in the peripheral blood have been carried out, but interpretation of these studies is difficult owing in part to inconsistency in marker usage. Despite these limitations, increased numbers of TReg cells have been seen consistently in disease tissues.

  • In vitro suppression cultures consistently show defects in TReg cell-mediated suppression in autoimmune diseases, with the exception of inflammatory bowel disease.

  • Resistance of effector T cells to suppression has been identified in type 1 diabetes, systemic lupus erythematosus and psoriasis.

  • Future studies that will enhance our understanding of the role of TReg cells in the development of autoimmunity should include improved analysis of the subsets of T cells with a CD4+CD25+FOXP3+ phenotype, as well as improved measures of suppression that will take into account factors that may be present in vivo at the site of inflammation, including the local antigen-presenting cells and cytokine environment.

  • In summary, defects in the number and suppressive function of CD4+CD25+FOXP3+ TReg cells have been identified in individuals with autoimmune disease. These findings now need to be extended to define the molecular mechanisms by which this form of tolerance is lost in the hope that this will guide the future development of therapies for these diseases.

Abstract

A lack of regulatory T (TReg) cells that express CD4, CD25 and forkhead box P3 (FOXP3) results in severe autoimmunity in both mice and humans. Since the discovery of TReg cells, there has been intense investigation aimed at determining how they protect an organism from autoimmunity and whether defects in their number or function contribute to the development of autoimmunity in model systems. The next phase of investigation — that is, to define the role that defects in TReg cells have in human autoimmunity — is now underway. This Review summarizes our progress so far towards understanding the role of CD4+CD25+FOXP3+ TReg cells in human autoimmune diseases and the impact that this knowledge might have on the diagnosis and treatment of these diseases.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Causes of impaired TReg cell-mediated suppression in autoimmunity.

Similar content being viewed by others

References

  1. Ochs, H. D., Gambineri, E. & Torgerson, T. R. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol. Res. 38, 112–121 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Sakaguchi, S. et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Baecher-Allan, C. et al. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253 (2001). One of the first papers to describe human CD4+CD25+ T Reg cells and to investigate their function.

    Article  CAS  PubMed  Google Scholar 

  5. Stephens, L. A. et al. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur. J. Immunol. 31, 1247–1254 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Taams, L. S. et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur. J. Immunol. 32, 1621–1630 (2002). This paper describes the antigen-specific nature of human T Reg cells.

    Article  CAS  PubMed  Google Scholar 

  7. Jiang, S. et al. Regulatory T cells and transplantation tolerance. Hum. Immunol. 67, 765–776 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Sakaguchi, S. et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995). This paper describes the ability of CD4+CD25+ T cells to suppress autoimmune disease.

    CAS  PubMed  Google Scholar 

  9. Tang, Q. et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199, 1455–1465 (2004). This paper shows the enhanced ability of antigen-specific T Reg cells to cure diabetes in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mottet, C., Uhlig, H. H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003). This paper shows that T Reg cells can cure colitis in a mouse model.

    Article  CAS  PubMed  Google Scholar 

  11. Liston, A. & Rudensky, A. Y. Thymic development and peripheral homeostasis of regulatory T cells. Curr. Opin. Immunol. 19, 176–185 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Darrasse-Jeze, G. et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206, 1853–1862 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wildin, R. S., Smyk-Pearson, S. & Filipovich, A. H. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet. 39, 537–545 (2002). This paper describes the syndrome IPEX and its relationship to loss of FOXP3 expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  16. Walker, M. R. et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J. Clin. Invest. 112, 1437–1443 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sakaguchi, S. et al. FOXP3+ regulatory T cells in the human immune system. Nature Rev. Immunol. 10, 490–500 (2010).

    Article  CAS  Google Scholar 

  19. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009). This paper refines our understanding of the subsets of CD4+FOXP3+ T cells, and has important implications with respect to the suppressive and proliferative capacity of T Reg cells.

    Article  CAS  PubMed  Google Scholar 

  22. Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nature Rev. Immunol. 8, 523–532 (2008).

    Article  CAS  Google Scholar 

  23. Bluestone, J. A. & Boehmer, H. Regulatory T cells. Semin. Immunol. 18, 77 (2006).

    Article  Google Scholar 

  24. Workman, C. J. et al. The development and function of regulatory T cells. Cell. Mol. Life Sci. 66, 2603–2622 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gregori, S. et al. Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J. Immunol. 171, 4040–4047 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. You, S. et al. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54, 1415–1422 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. D'Alise, A. M. et al. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc. Natl Acad. Sci. USA 105, 19857–19862 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Clough, L. E. et al. Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21. J. Immunol. 180, 5393–5401 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Korn, T. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nature Med. 13, 423–431 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Monk, C. R. et al. MRL/Mp CD4+, CD25− T cells show reduced sensitivity to suppression by CD4+, CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum. 52, 1180–1184 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Walker, L. S. Regulatory T cells overturned: the effectors fight back. Immunology 126, 466–474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kukreja, A. et al. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109, 131–140 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Putnam, A. L. et al. CD4+CD25high regulatory T cells in human autoimmune diabetes. J. Autoimmun. 24, 55–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Brusko, T. et al. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 56, 604–612 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Brusko, T. M. et al. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 54, 1407–1414 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Lindley, S. et al. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes 54, 92–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Long, S. A. et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T cells of type 1 diabetic subjects. Diabetes 59, 407–415 (2010). Based on the knowledge that genes involved in the IL-2 receptor signalling pathway are associated with susceptibility to type 1 diabetes, this paper identifies a defect in IL-2 receptor signalling in CD4+CD25+ T cells from patients with type 1 diabetes and, further, links this to a lack of T Reg cell persistence in vitro.

    Article  CAS  PubMed  Google Scholar 

  39. Marwaha, A. K. et al. Cutting edge: Increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J. Immunol. 185, 3814–3818 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Willcox, A. et al. Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol. 155, 173–181 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tree, T. I., Roep, B. O. & Peakman, M. A mini meta-analysis of studies on CD4+CD25+ T cells in human type 1 diabetes: report of the Immunology of Diabetes Society T Cell Workshop. Ann. NY Acad. Sci. 1079, 9–18 (2006). This paper reviews the early studies of T Reg cells in type 1 diabetes and discusses issues surrounding the assays used to assess T Reg cell function.

    Article  PubMed  Google Scholar 

  42. Schneider, A. et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J. Immunol. 181, 7350–7355 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Lawson, J. M. et al. Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin. Exp. Immunol. 154, 353–359 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McFarland, H. F. & Martin, R. Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunol. 8, 913–919 (2007).

    Article  CAS  Google Scholar 

  45. Kohm, A. P. et al. 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. 169, 4712–4716 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Viglietta, V. et al. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Putheti, P. et al. Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J. Clin. Immunol. 24, 155–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Haas, J. et al. Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis. J. Immunol. 179, 1322–1330 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Feger, U. et al. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin. Exp. Immunol. 147, 412–418 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Michel, L. et al. Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor α-chain are excluded from the analysis. J. Clin. Invest. 118, 3411–3419 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Venken, K. et al. Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J. Immunol. 180, 6411–6420 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Venken, K. et al. Compromised CD4+ CD25high 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 123, 79–89 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Kumar, M. et al. CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J. Neuroimmunol. 180, 178–184 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. de Andrés, C. et al. Interferon β-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J. Neuroimmunol. 182, 204–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Oh, U. et al. Regulatory T cells are reduced during anti-CD25 antibody treatment of multiple sclerosis. Arch. Neurol. 66, 471–479 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Haas, J. et al. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur. J. Immunol. 35, 3343–3352 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Huan, J. et al. Decreased FOXP3 levels in multiple sclerosis patients. J. Neurosci. Res. 81, 45–52 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Astier, A. L. et al. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J. Clin. Invest. 116, 3252–3257 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Venigalla, R. K. et al. Reduced CD4+, CD25− T cell sensitivity to the suppressive function of CD4+, CD25high, CD127−/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 58, 2120–2130 (2008).

    Article  PubMed  Google Scholar 

  61. Vargas-Rojas, M. I. et al. Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus 17, 289–294 (2008). References 60 and 61 were the first studies to clearly show effector T cell resistance in patients with autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  62. Gerli, R. et al. Identification of regulatory T cells in systemic lupus erythematosus. Autoimmun. Rev. 8, 426–430 (2009). An excellent review of the literature on T Reg cells and SLE.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  64. Miyara, M. et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J. Immunol. 175, 8392–8400 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Suen, J. L. et al. Altered homeostasis of CD4+ FoxP3+ regulatory T-cell subpopulations in systemic lupus erythematosus. Immunology 127, 196–205 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee, J. H. et al. Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 117, 280–286 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu, M. F. et al. Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand. J. Immunol. 59, 198–202 (2004).

    Article  PubMed  Google Scholar 

  69. Suarez, A. et al. Enrichment of CD4+ CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann. Rheum. Dis. 65, 1512–1517 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang, B. et al. Reduction of forkhead box P3 levels in CD4+CD25high T cells in patients with new-onset systemic lupus erythematosus. Clin. Exp. Immunol. 153, 182–187 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Alvarado-Sanchez, B. et al. Regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun. 27, 110–118 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  73. Yan, B. et al. Dysfunctional CD4+, CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-α-producing antigen-presenting cells. Arthritis Rheum. 58, 801–812 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Yates, J. et al. Natural regulatory T cells: number and function are normal in the majority of patients with lupus nephritis. Clin. Exp. Immunol. 153, 44–55 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Morgan, M. E. et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum. 48, 1452–1460 (2003).

    Article  PubMed  Google Scholar 

  76. Cao, D. et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur. J. Immunol. 33, 215–223 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Mottonen, M. et al. 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. 140, 360–367 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lawson, C. A. et al. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology 45, 1210–1217 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Han, G. M. et al. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell. Immunol. 253, 92–101 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J. Exp. Med. 200, 277–285 (2004). A thorough study of T Reg cell function in rheumatoid arthritis and during TNF-targeted therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Flores-Borja, F. et al. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 105, 19396–19401 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  83. Izcue, A. & Powrie, F. Special regulatory T-cell review: regulatory T cells and the intestinal tract — patrolling the frontier. Immunology 123, 6–10 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Saruta, M. et al. Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease. Clin. Immunol. 125, 281–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Takahashi, M. et al. An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis. Dig. Dis. Sci. 51, 677–686 (2006).

    Article  PubMed  Google Scholar 

  86. Maul, J. et al. Peripheral and intestinal regulatory CD4+ CD25high T cells in inflammatory bowel disease. Gastroenterology 128, 1868–1878 (2005). This is a well-controlled study of T Reg cell numbers in IBD that is notable for its use of inflammatory controls.

    Article  CAS  PubMed  Google Scholar 

  87. Li, Z. et al. Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. Inflamm. Bowel Dis. 16, 1299–1310 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Eastaff-Leung, N. et al. Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J. Clin. Immunol. 30, 80–89 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Rahman, M. K. et al. The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival. J. Immunol. 184, 7247–7256 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Uhlig, H. H. et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J. Immunol. 177, 5852–5860 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Sitohy, B. et al. Basal lymphoid aggregates in ulcerative colitis colon: a site for regulatory T cell action. Clin. Exp. Immunol. 151, 326–333 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hvas, C. L. et al. Discrete changes in circulating regulatory T cells during infliximab treatment of Crohn's disease. Autoimmunity 43, 325–333 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Ricciardelli, I. et al. Anti tumour necrosis-α therapy increases the number of FOXP3+ regulatory T cells in children affected by Crohn's disease. Immunology 125, 178–183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Holmen, N. et al. Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity. Inflamm. Bowel Dis. 12, 447–456 (2006).

    Article  PubMed  Google Scholar 

  95. Yu, Q. T. et al. Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis. Inflamm. Bowel Dis. 13, 191–199 (2007).

    Article  PubMed  Google Scholar 

  96. Kelsen, J. et al. FoxP3+CD4+CD25+ T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease. Clin. Exp. Immunol. 141, 549–557 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Makita, S. et al. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation. J. Immunol. 178, 4937–4946 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Fantini, M. C. et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology 136, 1308–1316 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Baadsgaard, O. et al. The role of the immune system in the pathogenesis of psoriasis. J. Invest. Dermatol. 95, S32–S34 (1990).

    Article  Google Scholar 

  100. Bata-Csorgo, Z. et al. Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. J. Clin. Invest. 95, 317–327 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yan, K. X. et al. Foxp3+ regulatory T cells and related cytokines differentially expressed in plaque vs. guttate psoriasis vulgaris. Br. J. Dermatol. 163, 48–56 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Bovenschen, H. J. et al. Identification of lesional CD4+ CD25+ Foxp3+ regulatory T cells in psoriasis. Dermatology 213, 111–117 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Zhang, L. et al. Increased Th17 cells are accompanied by FoxP3+ Treg cell accumulation and correlated with psoriasis disease severity. Clin. Immunol. 135, 108–117 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Chen, L. et al. Dynamic frequency of CD4+CD25+Foxp3+ Treg cells in psoriasis vulgaris. J. Dermatol. Sci. 51, 200–203 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Quaglino, P. et al. Circulating CD4+CD25brightFOXP3+ T cells are up-regulated by biological therapies and correlate with the clinical response in psoriasis patients. Dermatology 219, 250–258 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Diluvio, L. et al. Infliximab therapy induces increased polyclonality of CD4+CD25+ regulatory T cells in psoriasis. Br. J. Dermatol. 162, 895–897 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Sugiyama, H. et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol. 174, 164–173 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Goodman, W. A. et al. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J. Immunol. 183, 3170–3176 (2009). References 107 and 108 address the function of lesional T Reg cells in psoriasis and link these findings to T Reg cell- and tissue-specific mechanisms.

    Article  CAS  PubMed  Google Scholar 

  109. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Yates, J. et al. The maintenance of human CD4+ CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro. Int. Immunol. 19, 785–799 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Valencia, X. et al. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108, 253–261 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Thornton, A. M. et al. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 172, 6519–6523 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. King, I. L. & Segal, B. M. Cutting edge: IL-12 induces CD4+CD25− T cell activation in the presence of T regulatory cells. J. Immunol. 175, 641–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Ben Ahmed, M. et al. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J. Immunol. 182, 6763–6770 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Yang, J. et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc. Natl Acad. Sci. USA 104, 19954–19959 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Takeda, I. et al. Distinct roles for the OX40–OX40 ligand interaction in regulatory and nonregulatory T cells. J. Immunol. 172, 3580–3589 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Choi, B. K. et al. 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells. J. Leukoc. Biol. 75, 785–791 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Groux, H. et al. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J. Exp. Med. 184, 19–29 (1996).

    Article  CAS  PubMed  Google Scholar 

  119. Weiner, H. L. Induction and mechanism of action of transforming growth factor-β-secreting Th3 regulatory cells. Immunol. Rev. 182, 207–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Janson, P. C. et al. FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS ONE 3, e1612 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

J.H.B. is supported by grants from the US National Institutes of Health, the Juvenile Diabetes Research Foundation and the Alliance for Lupus Research.

Author information

Authors and Affiliations

  1. Translational Research Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, 98101, Washington, USA

    Jane Hoyt Buckner

Authors
  1. Jane Hoyt Buckner
    View author publications

    You can also search for this author inPubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Jane Hoyt Buckner's homepage

Glossary

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

(IPEX). A disease caused by mutations in the transcription factor forkhead box P3 (FOXP3) and characterized by refractory enteritis and, in some patients, autoimmune endocrinopathies, autoimmune diabetes and thyroiditis. Unlike scurfy mice, peripheral blood mononuclear cells from patients with IPEX fail to produce cytokines after in vitro stimulation.

Scurfy mice

A mouse strain with a spontaneous mutation in the transcription factor forkhead box P3 (FOXP3; also known as scurfin), which leads to a rapidly fatal lymphoproliferative disease, causing death by about 4 weeks of age. FOXP3-deficient mice lack regulatory T cells.

Non-obese diabetic mice

(NOD mice). NOD mice spontaneously develop type 1 diabetes mellitus as a result of autoreactive T cell-mediated destruction of pancreatic islet β-cells.

DO11.10 RIP-mOVA mice

A transgenic mouse model of type 1 diabetes in which a transgene encoding membrane-bound ovalbumin (mOVA) is expressed in the pancreas under the control of the rat insulin promoter (RIP) and therefore acts as a self antigen. Co-expression of a transgenic T cell receptor (DO11.10) in these mice leads to the development of spontaneous diabetes.

Experimental autoimmune encephalomyelitis

(EAE). An experimental mouse model of multiple sclerosis that is induced in susceptible animals by immunization with central nervous system antigens. EAE is an autoimmune disease that is mediated by CD4+ T helper 1 (TH1) cells and interleukin-17-producing TH17 cells that are reactive to components of the myelin sheath. The cells infiltrate the nervous parenchyma, release pro-inflammatory cytokines and chemokines, promote leukocyte infiltration and contribute to demyelination.

MRL–lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus. The lpr mutation causes a defect in CD95 (also known as FAS), preventing apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have yet to be identified.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation and is thought to result from an abnormal T cell-mediated response to commensal bacteria.

Ulcerative colitis

A mucosal inflammation involving the rectum and extending for a variable distance along the colon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buckner, J. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10, 849–859 (2010). https://doi.org/10.1038/nri2889

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2889

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing