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PMID: 23681097 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The plasticity and stability of regulatory T cells.

Nature reviews. Immunology ·Vol. 13 ·No. 6 ·2013-00-00 ·Pages 461-7

Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H

Abstract

Regulatory T (TReg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)(+) TReg cells are produced in the thymus and are also generated from conventional CD4(+) T cells in peripheral sites. It has been suggested that FOXP3(+) TReg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4(+) T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of TReg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells.

MeSH Terms
Animals CTLA-4 Antigen/immunology,metabolism Cell Differentiation/immunology Forkhead Transcription Factors/immunology,metabolism Humans Interleukin-2 Receptor alpha Subunit/immunology,metabolism Leukocyte Common Antigens/immunology,metabolism Mice T-Lymphocytes, Regulatory/cytology,immunology,metabolism Thymus Gland/cytology,immunology,metabolism
Chemicals
CTLA-4 Antigen CTLA4 protein, human FOXP3 protein, human Forkhead Transcription Factors Interleukin-2 Receptor alpha Subunit Leukocyte Common Antigens
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Sakaguchi Shimon
World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan. shimon@ifrec.osaka-u.ac.jp
Vignali Dario A A
Rudensky Alexander Y
Niec Rachel E
Waldmann Herman
References (48)
48 references, click to expand
  1. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo.
    Nat Immunol. 2009 Sep;10(9):1000-7 PMID: 19633673
  2. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.
    Science. 2003 Feb 14;299(5609):1033-6 PMID: 12532024
  3. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development.
    Immunity. 2012 Nov 16;37(5):785-99 PMID: 23123060
  4. Regulatory T cells and immune tolerance.
    Cell. 2008 May 30;133(5):775-87 PMID: 18510923
  5. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells.
    Immunity. 2012 Feb 24;36(2):262-75 PMID: 22326580
  6. Regulatory T cells: history and perspective.
    Methods Mol Biol. 2011;707:3-17 PMID: 21287325
  7. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance.
    J Exp Med. 2011 Sep 26;208(10):2043-53 PMID: 21875958
  8. Immune regulation by histone deacetylases: a focus on the alteration of FOXP3 activity.
    Immunol Cell Biol. 2012 Jan;90(1):95-100 PMID: 22124370
  9. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.
    Immunity. 2009 Jun 19;30(6):899-911 PMID: 19464196
  10. The development and function of regulatory T cells.
    Cell Mol Life Sci. 2009 Aug;66(16):2603-22 PMID: 19390784
  11. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection.
    Immunity. 2009 Nov 20;31(5):772-86 PMID: 19896394
  12. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
    Int Immunol. 1998 Dec;10(12):1969-80 PMID: 9885918
  13. How regulatory T cells work.
    Nat Rev Immunol. 2008 Jul;8(7):523-32 PMID: 18566595
  14. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner.
    J Immunol. 2009 May 15;182(10):6121-8 PMID: 19414764
  15. Regulatory T cells: mechanisms of differentiation and function.
    Annu Rev Immunol. 2012;30:531-64 PMID: 22224781
  16. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms.
    Sci Signal. 2012 Jun 19;5(229):ra45 PMID: 22715468
  17. Asymmetric T lymphocyte division in the initiation of adaptive immune responses.
    Science. 2007 Mar 23;315(5819):1687-91 PMID: 17332376
  18. Control of regulatory T cell development by the transcription factor Foxp3.
    Science. 2003 Feb 14;299(5609):1057-61 PMID: 12522256
  19. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions.
    Eur J Immunol. 2009 Apr;39(4):948-55 PMID: 19291701
  20. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.
    Nature. 2009 Mar 19;458(7236):351-6 PMID: 19182775
  21. Extrathymically generated regulatory T cells control mucosal TH2 inflammation.
    Nature. 2012 Feb 08;482(7385):395-9 PMID: 22318520
  22. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.
    J Exp Med. 1998 Jul 20;188(2):287-96 PMID: 9670041
  23. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner.
    Science. 2009 Nov 13;326(5955):986-91 PMID: 19797626
  24. DNA methylation controls Foxp3 gene expression.
    Eur J Immunol. 2008 Jun;38(6):1654-63 PMID: 18493985
  25. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.
    Nature. 2010 Feb 11;463(7282):808-12 PMID: 20072126
  26. FOXP3+ regulatory T cells in the human immune system.
    Nat Rev Immunol. 2010 Jul;10(7):490-500 PMID: 20559327
  27. Epigenetic control of the foxp3 locus in regulatory T cells.
    PLoS Biol. 2007 Feb;5(2):e38 PMID: 17298177
  28. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification.
    Cell. 2012 Sep 28;151(1):153-66 PMID: 23021222
  29. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells.
    Immunity. 2009 Jan 16;30(1):155-67 PMID: 19144320
  30. Enhancement of antigen-specific Treg vaccination in vivo.
    Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16246-51 PMID: 20805478
  31. Distinct inflammatory signals have physiologically divergent effects on epigenetic regulation of Foxp3 expression and Treg function.
    Am J Transplant. 2011 Feb;11(2):203-14 PMID: 21219575
  32. Plasticity of CD4(+) FoxP3(+) T cells.
    Curr Opin Immunol. 2009 Jun;21(3):281-5 PMID: 19500966
  33. Stability of the regulatory T cell lineage in vivo.
    Science. 2010 Sep 24;329(5999):1667-71 PMID: 20929851
  34. Regulatory T cells: recommendations to simplify the nomenclature.
    Nat Immunol. 2013 Apr;14(4):307-8 PMID: 23507634
  35. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3.
    Nat Immunol. 2007 Mar;8(3):277-84 PMID: 17220892
  36. Single-cell analysis of the human T regulatory population uncovers functional heterogeneity and instability within FOXP3+ cells.
    J Immunol. 2011 Jun 15;186(12):6788-97 PMID: 21576508
  37. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation.
    Nat Immunol. 2009 Jun;10(6):595-602 PMID: 19412181
  38. Multiple treg suppressive modules and their adaptability.
    Front Immunol. 2012 Jun 29;3:178 PMID: 22754556
  39. Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo.
    PLoS One. 2012;7(4):e35572 PMID: 22545118
  40. Regulatory T cells and Foxp3.
    Immunol Rev. 2011 May;241(1):260-8 PMID: 21488902
  41. A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells.
    Nat Immunol. 2012 Oct;13(10):972-80 PMID: 22961053
  42. Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8.
    Immunol Rev. 1996 Feb;149:5-33 PMID: 9005219
  43. Stability of regulatory T-cell lineage.
    Adv Immunol. 2011;112:1-24 PMID: 22118405
  44. Regulatory T cells and cancer.
    Curr Opin Immunol. 2007 Apr;19(2):217-23 PMID: 17306521
  45. Immune tolerance: are regulatory T cell subsets needed to explain suppression of autoimmunity?
    Bioessays. 2012 Jul;34(7):569-75 PMID: 22419393
  46. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis.
    Nat Med. 2013 Mar;19(3):322-8 PMID: 23396208
  47. Regulatory T cell lineage specification by the forkhead transcription factor foxp3.
    Immunity. 2005 Mar;22(3):329-41 PMID: 15780990
  48. Treg cells, life history, and diversity.
    Cold Spring Harb Perspect Biol. 2012 Sep 01;4(9):a007021 PMID: 22952391
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri3464
Email
shimon@ifrec.osaka-u.ac.jp
Published
2013-00-00
Epub
2013-00-17
Pages
461-7
Language
English
Region
England
NLM ID
101124169
Subset
IM
Grants
NIAID NIH HHS · R01 AI039480 · United States
NIGMS NIH HHS · GM07739 · United States
NIAID NIH HHS · R01 AI091977 · United States
NIAID NIH HHS · AI039480 · United States
NIAID NIH HHS · AI052199 · United States
NIDDK NIH HHS · R01 DK089125 · United States
NIGMS NIH HHS · T32 GM007739 · United States
NIAID NIH HHS · AI091977 · United States
NIDDK NIH HHS · DK089125 · United States
NINDS NIH HHS · 1F31NS073203-01 · United States
NIAID NIH HHS · R37 AI034206 · United States
NCI NIH HHS · CA21765 · United States
Medical Research Council · G1000215 · United Kingdom
External Links
PubMed source DOI: 10.1038/nri3464 View journal details
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