Home LiteratureArticle Details
PMID: 18997793 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells.

Nature immunology ·Vol. 9 ·No. 12 ·2008-12-00 ·Pages 1347-55

Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK

Abstract

Transcription factor Foxp3 is critical for generating regulatory T cells (T(reg) cells). Transforming growth factor-beta (TGF-beta) induces Foxp3 and suppressive T(reg) cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible T(reg) cells. Here we show that IL-4 blocked the generation of TGF-beta-induced Foxp3(+) T(reg) cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9(+)IL-10(+) T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9(+)IL-10(+) T cells into recombination-activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9(+)IL-10(+) T cells were transferred with CD45RB(hi) CD4(+) effector T cells. Thus IL-9(+)IL-10(+) T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.

MeSH Terms
Adoptive Transfer Animals Cell Differentiation/immunology Forkhead Transcription Factors/immunology,metabolism GATA3 Transcription Factor/immunology,metabolism Interleukin-10/immunology,metabolism Interleukin-4/immunology,metabolism Interleukin-9/immunology,metabolism Lymphocyte Activation/immunology Mice Mice, Transgenic STAT6 Transcription Factor/immunology,metabolism T-Lymphocyte Subsets/cytology,immunology T-Lymphocytes, Regulatory/cytology,immunology Transforming Growth Factor beta/immunology,metabolism
Chemicals
Forkhead Transcription Factors Foxp3 protein, mouse GATA3 Transcription Factor Gata3 protein, mouse Interleukin-9 STAT6 Transcription Factor Transforming Growth Factor beta Interleukin-10 Interleukin-4
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Dardalhon Valérie
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, USA.
Awasthi Amit
Kwon Hyoung
Galileos George
Gao Wenda
Sobel Raymond A
Mitsdoerffer Meike
Strom Terry B
Elyaman Wassim
Ho I-Cheng
Khoury Samia
Oukka Mohamed
Kuchroo Vijay K
References (45)
45 references, click to expand
  1. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity.
    J Immunol. 1996 Jun 15;156(12):4715-21 PMID: 8648117
  2. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus.
    J Exp Med. 1995 Mar 1;181(3):839-44 PMID: 7869046
  3. Interleukin-9 is involved in host protective immunity to intestinal nematode infection.
    Eur J Immunol. 1997 Oct;27(10):2536-40 PMID: 9368607
  4. Regulation of T helper cell differentiation by STAT molecules.
    J Leukoc Biol. 1998 Jul;64(1):2-5 PMID: 9665267
  5. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness.
    J Exp Med. 1998 Oct 5;188(7):1307-20 PMID: 9763610
  6. A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice.
    Infect Immun. 1999 Sep;67(9):4435-42 PMID: 10456884
  7. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells.
    J Exp Med. 2005 Mar 7;201(5):737-46 PMID: 15753207
  8. Essential role for CD103 in the T cell-mediated regulation of experimental colitis.
    J Exp Med. 2005 Oct 17;202(8):1051-61 PMID: 16216886
  9. Inducing and expanding regulatory T cell populations by foreign antigen.
    Nat Immunol. 2005 Dec;6(12):1219-27 PMID: 16244650
  10. Tr1 cells: from discovery to their clinical application.
    Semin Immunol. 2006 Apr;18(2):120-7 PMID: 16464609
  11. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
    Nature. 2006 May 11;441(7090):235-8 PMID: 16648838
  12. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation.
    Immunol Rev. 2006 Aug;212:256-71 PMID: 16903919
  13. Mast cells are essential intermediaries in regulatory T-cell tolerance.
    Nature. 2006 Aug 31;442(7106):997-1002 PMID: 16921386
  14. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
    Cell. 2006 Sep 22;126(6):1121-33 PMID: 16990136
  15. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis.
    J Immunol. 2006 Nov 1;177(9):5852-60 PMID: 17056509
  16. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse.
    Immunity. 2006 Dec;25(6):941-52 PMID: 17137799
  17. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression.
    Nature. 2007 Feb 15;445(7129):766-70 PMID: 17220876
  18. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells.
    Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18169-74 PMID: 17978190
  19. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells.
    Nat Immunol. 2007 Dec;8(12):1380-9 PMID: 17994022
  20. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10.
    Nat Immunol. 2007 Dec;8(12):1363-71 PMID: 17994025
  21. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.
    PLoS Biol. 2007 Dec;5(12):e329 PMID: 18162042
  22. Th17 cells: effector T cells with inflammatory properties.
    Semin Immunol. 2007 Dec;19(6):362-71 PMID: 18035554
  23. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces.
    Immunity. 2008 Apr;28(4):546-58 PMID: 18387831
  24. The biological functions of T helper 17 cell effector cytokines in inflammation.
    Immunity. 2008 Apr;28(4):454-67 PMID: 18400188
  25. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10.
    Immunity. 2008 Apr;28(4):468-76 PMID: 18400189
  26. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
    Nature. 2008 May 8;453(7192):236-40 PMID: 18368049
  27. Induction and effector functions of T(H)17 cells.
    Nature. 2008 Jun 19;453(7198):1051-7 PMID: 18563156
  28. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.
    Cell. 1997 May 16;89(4):587-96 PMID: 9160750
  29. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):6007-12 PMID: 10811896
  30. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis.
    J Immunol. 2000 Jun 15;164(12):6406-16 PMID: 10843696
  31. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.
    J Exp Med. 2000 Jul 17;192(2):295-302 PMID: 10899916
  32. Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis.
    Mol Cell Biol. 2002 Jan;22(1):117-26 PMID: 11739727
  33. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology.
    J Clin Invest. 2002 Jan;109(1):29-39 PMID: 11781348
  34. Control of regulatory T cell development by the transcription factor Foxp3.
    Science. 2003 Feb 14;299(5609):1057-61 PMID: 12522256
  35. IFN-alpha induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3.
    J Immunol. 2003 Jul 1;171(1):285-90 PMID: 12817009
  36. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.
    J Exp Med. 2003 Dec 15;198(12):1875-86 PMID: 14676299
  37. Control of autoimmunity by naturally arising regulatory CD4+ T cells.
    Adv Immunol. 2003;81:331-71 PMID: 14711059
  38. In vivo instruction of suppressor commitment in naive T cells.
    J Exp Med. 2004 May 17;199(10):1401-8 PMID: 15148338
  39. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40).
    J Exp Med. 1989 Jan 1;169(1):363-8 PMID: 2521242
  40. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice.
    Cell. 1990 Aug 10;62(3):457-67 PMID: 2116236
  41. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages.
    J Immunol. 1992 Mar 15;148(6):1792-6 PMID: 1541819
  42. A novel transcription factor, T-bet, directs Th1 lineage commitment.
    Cell. 2000 Mar 17;100(6):655-69 PMID: 10761931
  43. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients.
    J Clin Invest. 2000 May;105(9):1317-25 PMID: 10792007
  44. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice.
    J Exp Med. 1994 Jan 1;179(1):305-10 PMID: 8270873
  45. Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis.
    J Immunol. 1994 Jun 15;152(12):5949-56 PMID: 8207220
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1677
Published
2008-12-00
Epub
2008-00-09
Pages
1347-55
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2999006
Subset
IM
Grants
NINDS NIH HHS · 1P01NS38037-04 · United States
NINDS NIH HHS · 2R01NS35685-06 · United States
NIAID NIH HHS · R01 AI073542-01 · United States
NINDS NIH HHS · R01 NS045937 · United States
NIAID NIH HHS · R01 AI073542-03 · United States
NINDS NIH HHS · R37 NS030843 · United States
PHS HHS · 2P01A139671-07 · United States
NINDS NIH HHS · R01 NS035685 · United States
NIAID NIH HHS · R01AI073542-01 · United States
NINDS NIH HHS · 2R37NS30843-11 · United States
NIAID NIH HHS · P01 AI073748 · United States
PHS HHS · 1R01A144880-03 · United States
NINDS NIH HHS · 1R01NS045937-01 · United States
NINDS NIH HHS · R01 NS046414 · United States
NIAID NIH HHS · R01 AI073542 · United States
NIAID NIH HHS · R01 AI073542-02 · United States
NIAID NIH HHS · P01 AI073748-01A19002 · United States
NINDS NIH HHS · 1R01NS046414 · United States
NINDS NIH HHS · P01 NS038037 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1038/ni.1677 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2