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Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset

Nature Immunology volume 9, pages 13411346 (2008) | Download Citation

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Abstract

Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-β, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'TH-9' cells directly. Thus, transforming growth factor-β constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.

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References

  1. 1.

    et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

  2. 2.

    , & An epigenetic view of helper T cell differentiation. Nat. Immunol. 4, 616–623 (2003).

  3. 3.

    et al. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14, 205–215 (2001).

  4. 4.

    et al. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J. Exp. Med. 183, 901–913 (1996).

  5. 5.

    , & T cell heterogeneity: firmly fixed, predominantly plastic or merely malleable? Nat. Immunol. 9, 450–453 (2008).

  6. 6.

    , , & Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect. Immun. 66, 3832–3840 (1998).

  7. 7.

    , & Role of IL-9 in the pathophysiology of allergic diseases. J. Allergy Clin. Immunol. 107, 575–582 (2001).

  8. 8.

    et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442, 997–1002 (2006).

  9. 9.

    et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003).

  10. 10.

    & TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).

  11. 11.

    et al. A cascade of cytokines is responsible for IL-9 expression in human T cells. Involvement of IL-2, IL-4, and IL-10. J. Immunol. 154, 2624–2630 (1995).

  12. 12.

    et al. IL-4-independent regulation of in vivo IL-9 expression. J. Immunol. 159, 2616–2623 (1997).

  13. 13.

    et al. Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infect. Immun. 71, 2430–2438 (2003).

  14. 14.

    , & Functional plasticity in memory T helper cell responses. J. Immunol. 178, 4080–4088 (2007).

  15. 15.

    et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nat. Immunol. 4, 78–86 (2003).

  16. 16.

    et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

  17. 17.

    et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

  18. 18.

    TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia. Oncogene 24, 5701–5712 (2005).

  19. 19.

    & TGFβ1, a “Jack of all trades”: the link with pro-inflammatory IL-17-producing T cells. Trends Immunol. 27, 358–361 (2006).

  20. 20.

    , & Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006).

  21. 21.

    , & Cutting edge: TGF-β inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165, 4773–4777 (2000).

  22. 22.

    et al. Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses. Nat. Immunol. 5, 1157–1165 (2004).

  23. 23.

    et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

  24. 24.

    et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

  25. 25.

    , & GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J. Immunol. 176, 3470–3479 (2006).

  26. 26.

    , , & T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Proc. Natl. Acad. Sci. USA 95, 13823–13828 (1998).

  27. 27.

    et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12, 27–37 (2000).

  28. 28.

    et al. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-β and IL-4, and is inhibited by IFN-γ. J. Immunol. 153, 3989–3996 (1994).

  29. 29.

    & Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).

  30. 30.

    et al. Gastrointestinal nematode expulsion in IL-4 knockout mice is IL-13 dependent. Eur. J. Immunol. 30, 2083–2091 (2000).

  31. 31.

    , , & Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13. J. Exp. Med. 194, 355–364 (2001).

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Acknowledgements

We thank A. Rae and G. Preece for cell sorting; I. Baar for testing the specificity of goat anti-IL-9 by ELISA; and C. Watson (University of Cambridge) for spleens from Stat6−/− mice on a BALB/c background. Supported by the Fonds National de la Recherche Scientifique, Belgium (C.U. and J.v.S.).

Author information

Affiliations

  1. Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, London NW7 1AA, UK.

    • Marc Veldhoen
    • , Bruno Martin
    • , Christoph Wilhelm
    •  & Brigitta Stockinger
  2. Ludwig Institute for Cancer Research, Brussels Branch, Cellular Genetics Unit and Experimental Medicine Unit, Christian de Duve Institute of Cellular Pathology, Université de Louvain, 1200 Brussels, Belgium.

    • Catherine Uyttenhove
    •  & Jacques van Snick
  3. London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

    • Helena Helmby
  4. Institute of Medical Microbiology, University of Duisburg-Essen, D-45122 Essen, Germany.

    • Astrid Westendorf
    •  & Jan Buer

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Contributions

M.V. did and designed the experiments; C.U. and J.v.S. generated and labeled IL-9-specific monoclonal and polyclonal antibodies and did ELISA; H.H. did the trichuris experiments; B.M. contributed to experiments on deviation; A.W. and J.B. did the microarray analyses that were the starting basis of these studies; and B.S. designed experiments and wrote the manuscript.

Corresponding author

Correspondence to Brigitta Stockinger.

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DOI

https://doi.org/10.1038/ni.1659

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