Home LiteratureArticle Details
PMID: 19119024 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Late developmental plasticity in the T helper 17 lineage.

Immunity ·Vol. 30 ·No. 1 ·2009-01-16 ·Pages 92-107

Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT

Abstract

Development of T helper (Th) 17 cells requires transforming growth factor (TGF)-beta and interleukin (IL)-6 and is independent of the Th1 pathway. Although T cells that produce interferon (IFN)-gamma are a recognized feature of Th17 cell responses, mice deficient for STAT4 and T-bet-two prototypical Th1 transcription factors-are protected from autoimmunity associated with Th17 pathogenesis. To examine the fate and pathogenic potential of Th17 cells and origin of IFN-gamma-producing T cells that emerge during Th17 immunity, we developed IL-17F reporter mice that identify cells committed to expression of IL-17F and IL-17A. Th17 cells required TGF-beta for sustained expression of IL-17F and IL-17A. In the absence of TGF-beta, both IL-23 and IL-12 acted to suppress IL-17 and enhance IFN-gamma production in a STAT4- and T-bet-dependent manner, albeit with distinct efficiencies. These results support a model of late Th17 developmental plasticity with implications for autoimmunity and host defense.

MeSH Terms
Animals Cell Lineage/immunology Cells, Cultured Flow Cytometry Interferon-gamma/metabolism Interleukin-17/metabolism Interleukin-23/metabolism Mice Mice, Knockout T-Lymphocyte Subsets/immunology Th1 Cells/immunology Th2 Cells/immunology Transforming Growth Factor beta/metabolism
Chemicals
Interleukin-17 Interleukin-23 Transforming Growth Factor beta Interferon-gamma
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Lee Yun Kyung
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Turner Henrietta
Maynard Craig L
Oliver James R
Chen Dongquan
Elson Charles O
Weaver Casey T
References (60)
60 references, click to expand
  1. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding.
    EMBO J. 2001 Oct 1;20(19):5332-41 PMID: 11574464
  2. Th17: an effector CD4 T cell lineage with regulatory T cell ties.
    Immunity. 2006 Jun;24(6):677-688 PMID: 16782025
  3. IL-12- and IL-23-induced T helper cell subsets: birds of the same feather flock together.
    J Exp Med. 2005 Jan 17;201(2):169-71 PMID: 15657286
  4. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.
    Nat Immunol. 2007 Dec;8(12):1390-7 PMID: 17994024
  5. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis.
    J Clin Invest. 2001 Sep;108(5):739-47 PMID: 11544280
  6. Memory CD4 T cells emerge from effector T-cell progenitors.
    Nature. 2008 Mar 20;452(7185):356-60 PMID: 18322463
  7. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
    Nature. 2006 May 11;441(7090):235-8 PMID: 16648838
  8. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
    Immunity. 2006 Feb;24(2):179-89 PMID: 16473830
  9. TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet.
    J Immunol. 2005 May 15;174(10):5950-8 PMID: 15879087
  10. T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype.
    Blood. 2006 Sep 1;108(5):1595-601 PMID: 16670261
  11. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens.
    Nat Med. 2008 Mar;14(3):282-9 PMID: 18264109
  12. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.
    Int Immunol. 1993 Nov;5(11):1461-71 PMID: 7903159
  13. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses.
    Cell Res. 2007 May;17(5):435-40 PMID: 17452998
  14. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.
    J Exp Med. 1994 Feb 1;179(2):589-600 PMID: 7905019
  15. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
    Nat Immunol. 2005 Nov;6(11):1133-41 PMID: 16200068
  16. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.
    J Biol Chem. 2007 Mar 30;282(13):9358-9363 PMID: 17277312
  17. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
    J Exp Med. 2005 Jan 17;201(2):233-40 PMID: 15657292
  18. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
    Nat Immunol. 2007 Sep;8(9):967-74 PMID: 17581537
  19. An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment.
    J Immunol. 2007 Dec 1;179(11):7791-9 PMID: 18025225
  20. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells.
    Nat Immunol. 2006 Sep;7(9):929-36 PMID: 16906167
  21. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice.
    Gastroenterology. 2007 Jun;132(7):2359-70 PMID: 17570211
  22. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.
    Immunity. 2000 Nov;13(5):715-25 PMID: 11114383
  23. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination.
    J Immunol. 2002 Dec 15;169(12):7104-10 PMID: 12471147
  24. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity.
    J Immunol. 2007 Oct 1;179(7):4313-7 PMID: 17878325
  25. IL-17 family cytokines and the expanding diversity of effector T cell lineages.
    Annu Rev Immunol. 2007;25:821-52 PMID: 17201677
  26. Th17 cell differentiation: the long and winding road.
    Immunity. 2008 Apr;28(4):445-53 PMID: 18400187
  27. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
    Nature. 2003 Feb 13;421(6924):744-8 PMID: 12610626
  28. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells.
    J Exp Med. 1996 Jun 1;183(6):2669-74 PMID: 8676088
  29. Phenotypic and functional features of human Th17 cells.
    J Exp Med. 2007 Aug 6;204(8):1849-61 PMID: 17635957
  30. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.
    J Biol Chem. 2003 Jan 17;278(3):1910-4 PMID: 12417590
  31. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
    J Exp Med. 2003 Dec 15;198(12):1951-7 PMID: 14662908
  32. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression.
    J Immunol. 2000 Nov 1;165(9):4773-7 PMID: 11045997
  33. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.
    Immunity. 2008 Jan;28(1):29-39 PMID: 18164222
  34. Transforming growth factor-beta induces development of the T(H)17 lineage.
    Nature. 2006 May 11;441(7090):231-4 PMID: 16648837
  35. Role of Th1 and Th17 cells in organ-specific autoimmunity.
    J Autoimmun. 2008 Nov;31(3):252-6 PMID: 18502610
  36. Understanding the IL-23-IL-17 immune pathway.
    Trends Immunol. 2006 Jan;27(1):17-23 PMID: 16290228
  37. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis.
    J Immunol. 1996 Oct 15;157(8):3223-7 PMID: 8871615
  38. Interleukin-17 family members and inflammation.
    Immunity. 2004 Oct;21(4):467-76 PMID: 15485625
  39. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis.
    Immunity. 2008 Apr;28(4):559-70 PMID: 18400195
  40. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.
    J Clin Invest. 2006 May;116(5):1317-26 PMID: 16670771
  41. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12.
    J Clin Invest. 2002 Aug;110(4):493-7 PMID: 12189243
  42. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis.
    J Exp Med. 2004 Jul 5;200(1):79-87 PMID: 15238607
  43. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
    J Immunol. 2002 Jun 1;168(11):5699-708 PMID: 12023369
  44. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection.
    Immunity. 2003 Nov;19(5):645-55 PMID: 14614852
  45. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10.
    Nat Immunol. 2007 Sep;8(9):931-41 PMID: 17694059
  46. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.
    Immunity. 2007 Mar;26(3):371-81 PMID: 17363300
  47. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.
    Nature. 2007 Jul 26;448(7152):484-487 PMID: 17581588
  48. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
    Nature. 2007 Feb 8;445(7128):648-51 PMID: 17187052
  49. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.
    J Exp Med. 2002 May 6;195(9):1129-43 PMID: 11994418
  50. Differentiation and function of Th17 T cells.
    Curr Opin Immunol. 2007 Jun;19(3):281-6 PMID: 17433650
  51. Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation.
    EMBO J. 2007 Mar 7;26(5):1292-302 PMID: 17304212
  52. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE).
    J Immunol. 1996 Jan 1;156(1):5-7 PMID: 8598493
  53. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.
    Nat Immunol. 2007 Apr;8(4):369-77 PMID: 17351619
  54. Stat3 and Stat4 direct development of IL-17-secreting Th cells.
    J Immunol. 2007 Apr 15;178(8):4901-7 PMID: 17404271
  55. T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis.
    J Exp Med. 2002 Jan 7;195(1):71-84 PMID: 11781367
  56. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system.
    J Immunol. 2003 Feb 15;170(4):2153-60 PMID: 12574388
  57. Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells.
    J Immunol. 1998 Aug 15;161(4):1664-70 PMID: 9712029
  58. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.
    Nature. 2007 Jul 26;448(7152):480-3 PMID: 17581589
  59. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
    Nat Immunol. 2005 Nov;6(11):1123-32 PMID: 16200070
  60. 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
Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2008.11.005
Published
2009-01-16
Pages
92-107
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3607320
Subset
IM
Grants
NIAID NIH HHS · R01 AI077574-04 · United States
NIAID NIH HHS · R01 AI077574-02 · United States
NIDDK NIH HHS · P01 DK071176-03 · United States
NIAID NIH HHS · R01 AI035783 · United States
NIAID NIH HHS · R01 AI077574-01A2 · United States
NIDDK NIH HHS · P01 DK071176-04S1 · United States
NIDDK NIH HHS · P01 DK071176-04 · United States
NIDDK NIH HHS · R24 DK064400 · United States
NIAID NIH HHS · R01 AI077574 · United States
NIDDK NIH HHS · P01 DK071176-05 · United States
NIAID NIH HHS · R01 AI077574-03 · United States
NIDDK NIH HHS · P01 DK071176 · United States
NIDDK NIH HHS · P01 DK071176-02 · United States
NIDDK NIH HHS · P01 DK071176-06 · United States
NIDDK NIH HHS · P01 DK071176-07 · United States
NIDDK NIH HHS · P01 DK071176-08 · United States
NIDDK NIH HHS · P01 DK071176-01 · United States
Databases
GEO
GSE14026
Corrections
CommentIn
PMID: 19144312
External Links
PubMed source DOI: 10.1016/j.immuni.2008.11.005 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: [email protected]

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