Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Immunology volume 9, pages 1341–1346 (2008)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TGF-β and IL-4 drive 'TH-9' differentiation.
Figure 2: IL-9 expression distinct from that of the profiles of TH1, TH2, iTreg and TH-17 effector cells.
Figure 3: TGF-β 'reprograms' committed TH2 cells to a 'TH-9' profile.
Figure 4: TGF-β responsiveness is essential for IL-9 production in vivo.

Similar content being viewed by others

References

  1. Mosmann, T.R. 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).

    CAS  Google Scholar 

  2. Ansel, K.M., Lee, D.U. & Rao, A. An epigenetic view of helper T cell differentiation. Nat. Immunol. 4, 616–623 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. O'Shea, J.J., Hunter, C.A. & Germain, R.N. T cell heterogeneity: firmly fixed, predominantly plastic or merely malleable? Nat. Immunol. 9, 450–453 (2008).

    Article  CAS  Google Scholar 

  6. Faulkner, H., Renauld, J.C., Van Snick, J. & Grencis, R.K. Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect. Immun. 66, 3832–3840 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Soussi-Gounni, A., Kontolemos, M. & Hamid, Q. Role of IL-9 in the pathophysiology of allergic diseases. J. Allergy Clin. Immunol. 107, 575–582 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Stetson, D.B. 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).

    Article  CAS  Google Scholar 

  10. O'Garra, A. & Vieira, P. TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).

    Article  CAS  Google Scholar 

  11. Houssiau, F.A. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Khan, W.I. 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).

    Article  CAS  Google Scholar 

  14. Krawczyk, C.M., Shen, H. & Pearce, E.J. Functional plasticity in memory T helper cell responses. J. Immunol. 178, 4080–4088 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Harrington, L.E. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Li, M.O., Sanjabi, S. & Flavell, R.A. 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).

    Article  CAS  Google Scholar 

  21. Gorelik, L., Fields, P.E. & Flavell, R.A. Cutting edge: TGF-β inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165, 4773–4777 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. McGeachy, M.J. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Shoemaker, J., Saraiva, M. & O'Garra, A. GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J. Immunol. 176, 3470–3479 (2006).

    Article  CAS  Google Scholar 

  26. Dent, A.L., Hu-Li, J., Paul, W.E. & Staudt, L.M. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Schmitt, E. 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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Helmby, H., Takeda, K., Akira, S. & Grencis, R.K. Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13. J. Exp. Med. 194, 355–364 (2001).

    Article  CAS  Google Scholar 

Download references

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

Authors and 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

Authors
  1. Marc Veldhoen
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Catherine Uyttenhove
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Jacques van Snick
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Helena Helmby
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Astrid Westendorf
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Jan Buer
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Bruno Martin
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Christoph Wilhelm
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Brigitta Stockinger
    View author publications

    You can also search for this author inPubMed Google Scholar

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 820 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veldhoen, M., Uyttenhove, C., van Snick, J. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset. Nat Immunol 9, 1341–1346 (2008). https://doi.org/10.1038/ni.1659

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy