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PMID: 16630018 Published · ppublish English Journal Article Review

Regulatory T cells in human disease and their potential for therapeutic manipulation.

Immunology ·Vol. 118 ·No. 1 ·2006-05-00 ·Pages 1-9

Taams LS, Palmer DB, Akbar AN, Robinson DS, Brown Z, Hawrylowicz CM

Abstract

Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7-8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity.

MeSH Terms
Autoimmunity Humans Immune System Diseases/immunology,therapy Immune Tolerance Immunotherapy/methods Infections/immunology Neoplasms/immunology T-Lymphocytes, Regulatory/immunology
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Taams Leonie S
Division of Infection, Immunity and Inflammatory Diseases, Guy's Hospital, King's College London, London, UK. [email protected]
Palmer Donald B
Akbar Arne N
Robinson Douglas S
Brown Zarin
Hawrylowicz Catherine M
References (89)
89 references, click to expand
  1. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity.
    J Immunol. 1999 Nov 15;163(10):5211-8 PMID: 10553041
  2. Interleukin-10-secreting "regulatory" T cells induced by glucocorticoids and beta2-agonists.
    Am J Respir Cell Mol Biol. 2005 Jul;33(1):105-11 PMID: 15845862
  3. Glucocorticoids drive human CD8(+) T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production.
    Eur J Immunol. 2000 Aug;30(8):2344-54 PMID: 10940925
  4. CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid.
    Arthritis Rheum. 2004 Sep;50(9):2775-85 PMID: 15457445
  5. Natural regulatory T cells in infectious disease.
    Nat Immunol. 2005 Apr;6(4):353-60 PMID: 15785761
  6. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease.
    Lancet. 2004 Feb 21;363(9409):608-15 PMID: 14987885
  7. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals.
    J Immunol. 2003 Dec 1;171(11):5760-8 PMID: 14634084
  8. T cell epitope immunotherapy induces a CD4+ T cell population with regulatory activity.
    PLoS Med. 2005 Mar;2(3):e78 PMID: 15783262
  9. Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease.
    J Immunol. 2004 Aug 1;173(3):2118-25 PMID: 15265948
  10. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection.
    Hepatology. 2003 Dec;38(6):1437-48 PMID: 14647055
  11. Exposure to myeloma cell lysates affects the immune competence of dendritic cells and favors the induction of Tr1-like regulatory T cells.
    Eur J Immunol. 2005 Apr;35(4):1155-63 PMID: 15761844
  12. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist.
    Eur J Immunol. 2003 Mar;33(3):626-38 PMID: 12616483
  13. Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production.
    J Allergy Clin Immunol. 2003 Apr;111(4):862-8 PMID: 12704370
  14. Depletion of regulatory T cells in HIV infection is associated with immune activation.
    J Immunol. 2005 Apr 1;174(7):4407-14 PMID: 15778406
  15. Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals.
    Infect Immun. 2003 Apr;71(4):1755-62 PMID: 12654789
  16. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans.
    Hum Immunol. 2005 Jan;66(1):13-20 PMID: 15620457
  17. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells.
    J Exp Med. 1994 Feb 1;179(2):493-502 PMID: 7905018
  18. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients.
    Blood. 2004 Nov 15;104(10):3249-56 PMID: 15271794
  19. Allergy, parasites, and the hygiene hypothesis.
    Science. 2002 Apr 19;296(5567):490-4 PMID: 11964470
  20. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
    Nat Genet. 2001 Jan;27(1):20-1 PMID: 11137993
  21. Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects.
    Eur J Immunol. 1997 May;27(5):1131-9 PMID: 9174602
  22. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.
    J Exp Med. 2004 Jun 7;199(11):1567-75 PMID: 15173208
  23. Regulatory T cells in transplantation tolerance.
    Nat Rev Immunol. 2003 Mar;3(3):199-210 PMID: 12658268
  24. Role of interleukin 10 in specific immunotherapy.
    J Clin Invest. 1998 Jul 1;102(1):98-106 PMID: 9649562
  25. Dendritic cells as a tool to induce anergic and regulatory T cells.
    Trends Immunol. 2001 Jul;22(7):394-400 PMID: 11429324
  26. Cow's milk-specific T-cell reactivity of children with and without persistent cow's milk allergy: key role for IL-10.
    J Allergy Clin Immunol. 2004 May;113(5):932-9 PMID: 15131577
  27. CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.
    J Immunol. 2004 May 15;172(10):6435-43 PMID: 15128835
  28. In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures.
    Blood. 2004 Jul 15;104(2):453-61 PMID: 15031211
  29. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells.
    J Exp Med. 2001 Jan 15;193(2):233-8 PMID: 11208863
  30. Regulatory T cells: friend or foe in immunity to infection?
    Nat Rev Immunol. 2004 Nov;4(11):841-55 PMID: 15516964
  31. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines.
    J Exp Med. 2002 Mar 4;195(5):603-16 PMID: 11877483
  32. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation.
    J Immunol. 2002 May 1;168(9):4272-6 PMID: 11970966
  33. Peptide-based therapeutic vaccines for allergic and autoimmune diseases.
    Nat Med. 2005 Apr;11(4 Suppl):S69-76 PMID: 15812493
  34. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.
    Nat Immunol. 2005 Apr;6(4):345-52 PMID: 15785760
  35. Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus.
    BMC Immunol. 2003 Feb 22;4:2 PMID: 12597780
  36. CD4+ CD25+ suppressor T cells: more questions than answers.
    Nat Rev Immunol. 2002 Jun;2(6):389-400 PMID: 12093005
  37. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis.
    Blood. 2005 Jan 15;105(2):735-41 PMID: 15454488
  38. Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis.
    Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4228-33 PMID: 15024101
  39. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status.
    J Exp Med. 2004 Aug 2;200(3):331-43 PMID: 15280419
  40. Foxp3 and natural regulatory T cells: key to a cell lineage?
    Immunity. 2003 Aug;19(2):165-8 PMID: 12932350
  41. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.
    J Exp Med. 2001 Sep 17;194(6):823-32 PMID: 11560997
  42. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II.
    J Exp Med. 2004 May 3;199(9):1285-91 PMID: 15117972
  43. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance.
    J Immunol. 2001 Aug 15;167(4):1945-53 PMID: 11489974
  44. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells.
    Immunol Rev. 2001 Aug;182:207-14 PMID: 11722636
  45. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8372-7 PMID: 12826605
  46. Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo.
    Blood. 2003 Sep 15;102(6):2180-6 PMID: 12775574
  47. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells.
    J Clin Invest. 2003 Nov;112(9):1437-43 PMID: 14597769
  48. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation.
    Ann Thorac Surg. 1997 Jan;63(1):269-76 PMID: 8993291
  49. Increase of regulatory T cells in the peripheral blood of cancer patients.
    Clin Cancer Res. 2003 Feb;9(2):606-12 PMID: 12576425
  50. Fluticasone propionate increases CD4CD25 T regulatory cell suppression of allergen-stimulated CD4CD25 T cells by an IL-10-dependent mechanism.
    J Allergy Clin Immunol. 2004 Aug;114(2):296-301 PMID: 15316506
  51. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.
    Diabetes. 2005 Jun;54(6):1763-9 PMID: 15919798
  52. 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 May;140(2):360-7 PMID: 15807863
  53. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection.
    Hepatology. 2004 Nov;40(5):1062-71 PMID: 15486925
  54. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.
    Nat Genet. 2001 Jan;27(1):18-20 PMID: 11137992
  55. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells.
    Blood. 2004 Aug 1;104(3):895-903 PMID: 15090447
  56. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens.
    J Virol. 2004 Mar;78(5):2454-9 PMID: 14963140
  57. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
    Nat Med. 2004 Sep;10(9):942-9 PMID: 15322536
  58. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells.
    J Immunol. 2004 Jul 15;173(2):1444-53 PMID: 15240741
  59. Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients.
    Infect Immun. 2005 Jan;73(1):523-31 PMID: 15618192
  60. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes.
    Diabetes. 2005 Jan;54(1):92-9 PMID: 15616015
  61. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma.
    Cancer Res. 2005 Mar 15;65(6):2457-64 PMID: 15781662
  62. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection.
    Hepatology. 2005 Apr;41(4):771-8 PMID: 15791617
  63. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy.
    J Exp Med. 2004 Aug 2;200(3):277-85 PMID: 15280421
  64. Regulatory T cells in the control of immune pathology.
    Nat Immunol. 2001 Sep;2(9):816-22 PMID: 11526392
  65. Cat allergen peptide immunotherapy reduces CD4(+) T cell responses to cat allergen but does not alter suppression by CD4(+) CD25(+) T cells: a double-blind placebo-controlled study.
    Allergy. 2004 Oct;59(10):1097-101 PMID: 15355469
  66. Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season.
    Clin Exp Allergy. 2004 Sep;34(9):1364-72 PMID: 15347368
  67. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells.
    Eur J Immunol. 2002 Jun;32(6):1621-30 PMID: 12115645
  68. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.
    J Exp Med. 2004 Apr 5;199(7):971-9 PMID: 15067033
  69. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.
    N Engl J Med. 2005 Jun 23;352(25):2598-608 PMID: 15972866
  70. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells.
    J Immunol. 2003 Apr 15;170(8):3939-43 PMID: 12682220
  71. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma.
    J Allergy Clin Immunol. 2004 Dec;114(6):1425-33 PMID: 15577848
  72. Tregs and allergic disease.
    J Clin Invest. 2004 Nov;114(10):1389-97 PMID: 15545986
  73. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma.
    Nat Rev Immunol. 2005 Apr;5(4):271-83 PMID: 15775993
  74. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group.
    Nat Med. 2000 Oct;6(10):1176-82 PMID: 11017151
  75. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients.
    J Allergy Clin Immunol. 2002 Feb;109(2):369-70 PMID: 11842311
  76. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.
    J Clin Invest. 2006 Jan;116(1):146-55 PMID: 16341266
  77. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.
    J Immunol. 2005 Jan 1;174(1):164-73 PMID: 15611238
  78. Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy.
    J Exp Med. 2004 Jun 21;199(12):1679-88 PMID: 15197226
  79. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia.
    J Exp Med. 2005 Jun 6;201(11):1793-803 PMID: 15939793
  80. Transforming growth factor-beta in T-cell biology.
    Nat Rev Immunol. 2002 Jan;2(1):46-53 PMID: 11905837
  81. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes.
    Nat Med. 2003 Sep;9(9):1202-8 PMID: 12937416
  82. Regulatory T cells and organ transplantation.
    Semin Immunol. 2004 Apr;16(2):119-26 PMID: 15036235
  83. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma.
    J Immunol. 2002 Sep 1;169(5):2756-61 PMID: 12193750
  84. An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells.
    J Exp Med. 2005 Apr 18;201(8):1293-305 PMID: 15837814
  85. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma.
    Blood. 2004 Mar 1;103(5):1755-62 PMID: 14604957
  86. Type 1 T regulatory cells.
    Immunol Rev. 2001 Aug;182:68-79 PMID: 11722624
  87. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease.
    Arthritis Res Ther. 2004;6(4):R335-46 PMID: 15225369
  88. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage.
    J Clin Invest. 2004 Nov;114(10):1372-8 PMID: 15545984
  89. Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis).
    Microbes Infect. 2002 Nov;4(13):1291-300 PMID: 12443893
Article Info
Journal
Immunology
Abbr.
Immunology
ISSN
0019-2805
DOI
10.1111/j.1365-2567.2006.02348.x
Email
[email protected]
Published
2006-05-00
Pages
1-9
Language
English
Region
England
NLM ID
0374672
PMCID
PMC1782265
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1365-2567.2006.02348.x PMC Full Text View journal details
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