Generation of pathogenic TH17 cells in the absence of TGF-β signalling (original) (raw)

Nature volume 467, pages 967–971 (2010)Cite this article

Subjects

Abstract

CD4+ T-helper cells that selectively produce interleukin (IL)-17 (TH17), are critical for host defence and autoimmunity1,2,3,4. Although crucial for TH17 cells _in viv_o5,6, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification7,8,9,10. Here we show that TH17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated TH17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet+RORγt+ TH17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred TH17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for TH17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The ChIP-seq and microarray data sets are deposited in Gene Expression Omnibus database under accession numbers GSE23505 and GSE23681.

References

  1. Miossec, P., Korn, T. & Kuchroo, V. K. Interleukin-17 and type 17 helper T cells. N. Engl. J. Med. 361, 888–898 (2009)
    Article CAS Google Scholar
  2. Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007)
    Article CAS Google Scholar
  3. Stockinger, B. & Veldhoen, M. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 19, 281–286 (2007)
    Article CAS Google Scholar
  4. Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009)
    Article CAS Google Scholar
  5. Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003)
    Article ADS CAS Google Scholar
  6. McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo . Nature Immunol. 10, 314–324 (2009)
    Article CAS Google Scholar
  7. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006)
    Article CAS Google Scholar
  8. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006)
    Article ADS CAS Google Scholar
  9. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006)
    Article CAS Google Scholar
  10. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)
    Article ADS CAS Google Scholar
  11. Veldhoen, M., Hocking, R. J., Flavell, R. A. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nature Immunol. 7, 1151–1156 (2006)
    Article CAS Google Scholar
  12. Liu, Y. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nature Immunol. 9, 632–640 (2008)
    Article ADS CAS Google Scholar
  13. Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009)
    Article CAS Google Scholar
  14. Das, J. et al. Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation. J. Exp. Med. 206, 2407–2416 (2009)
    Article CAS Google Scholar
  15. Bettelli, E. et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004)
    Article CAS Google Scholar
  16. Lochner, M. et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008)
    Article CAS Google Scholar
  17. Yang, Y. et al. T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J. Exp. Med. 206, 1549–1564 (2009)
    Article CAS Google Scholar
  18. Aggarwal, S., Ghilardi, N., Xie, M. H., de Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003)
    Article CAS Google Scholar
  19. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005)
    Article CAS Google Scholar
  20. 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. Nature Immunol. 6, 1123–1132 (2005)
    Article CAS Google Scholar
  21. 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. Nature Immunol. 8, 1390–1397 (2007)
    Article CAS Google Scholar
  22. Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol. 8, 950–957 (2007)
    Article CAS Google Scholar
  23. Chen, Z., Tato, C. M., Muul, L., Laurence, A. & O’Shea, J. J. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 56, 2936–2946 (2007)
    Article CAS Google Scholar
  24. Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nature Immunol. 8, 942–949 (2007)
    Article CAS Google Scholar
  25. Elyaman, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl Acad. Sci. USA 106, 12885–12890 (2009)
    Article ADS CAS Google Scholar
  26. Nowak, E. C. et al. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 206, 1653–1660 (2009)
    Article CAS Google Scholar
  27. Gutcher, I., Urich, E., Wolter, K., Prinz, M. & Becher, B. Interleukin 18-independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation. Nature Immunol. 7, 946–953 (2006)
    Article CAS Google Scholar
  28. Lord, G. M. et al. T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106, 3432–3439 (2005)
    Article CAS Google Scholar
  29. Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature Immunol. 10, 595–602 (2009)
    Article CAS Google Scholar
  30. Kebir, H. et al. Preferential recruitment of interferon-γ-expressing TH17 cells in multiple sclerosis. Ann. Neurol. 66, 390–402 (2009)
    Article ADS CAS Google Scholar
  31. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009)
    Article Google Scholar
  32. Durant, L. et al. Diverse STAT3 targets contribute to T cell pathogenicity and homeostasis. Immunity 32, 605–615 (2010)
    Article CAS Google Scholar
  33. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007)
    Article CAS Google Scholar
  34. Wei, L., Laurence, A., Elias, K. M. & O’Shea, J. J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem. 282, 34605–34610 (2007)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank J. Simone, J. Lay (Flow Cytometry Section, NIAMS) and the NIAMS LACU staff for technical support. This work has been supported by the Intramural Research Programs of NIAMS, NIDCR and NIAID.

Author information

Author notes

  1. Arian Laurence and Xiang-Ping Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Kamran Ghoreschi, Arian Laurence, Xiang-Ping Yang, Haydeé L. Ramos, Lai Wei, Yuka Kanno, Wendy T. Watford & John J. O’Shea
  2. Merck Research Laboratories, Palo Alto, 94304, California, USA
    Cristina M. Tato, Mandy J. McGeachy & Daniel J. Cua
  3. Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Joanne E. Konkel & WanJun Chen
  4. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Todd S. Davidson, Qian Chen & Ethan M. Shevach
  5. Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Nicolas Bouladoux, John R. Grainger & Yasmine Belkaid
  6. Biodata Mining and Discovery Section, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Hong-Wei Sun
  7. Institut Pasteur, Lymphoid Tissue Development Unit, Paris, 75724, France
    Gérard Eberl

Authors

  1. Kamran Ghoreschi
    You can also search for this author inPubMed Google Scholar
  2. Arian Laurence
    You can also search for this author inPubMed Google Scholar
  3. Xiang-Ping Yang
    You can also search for this author inPubMed Google Scholar
  4. Cristina M. Tato
    You can also search for this author inPubMed Google Scholar
  5. Mandy J. McGeachy
    You can also search for this author inPubMed Google Scholar
  6. Joanne E. Konkel
    You can also search for this author inPubMed Google Scholar
  7. Haydeé L. Ramos
    You can also search for this author inPubMed Google Scholar
  8. Lai Wei
    You can also search for this author inPubMed Google Scholar
  9. Todd S. Davidson
    You can also search for this author inPubMed Google Scholar
  10. Nicolas Bouladoux
    You can also search for this author inPubMed Google Scholar
  11. John R. Grainger
    You can also search for this author inPubMed Google Scholar
  12. Qian Chen
    You can also search for this author inPubMed Google Scholar
  13. Yuka Kanno
    You can also search for this author inPubMed Google Scholar
  14. Wendy T. Watford
    You can also search for this author inPubMed Google Scholar
  15. Hong-Wei Sun
    You can also search for this author inPubMed Google Scholar
  16. Gérard Eberl
    You can also search for this author inPubMed Google Scholar
  17. Ethan M. Shevach
    You can also search for this author inPubMed Google Scholar
  18. Yasmine Belkaid
    You can also search for this author inPubMed Google Scholar
  19. Daniel J. Cua
    You can also search for this author inPubMed Google Scholar
  20. WanJun Chen
    You can also search for this author inPubMed Google Scholar
  21. John J. O’Shea
    You can also search for this author inPubMed Google Scholar

Contributions

K.G. designed, performed, analysed and interpreted all the experiments and wrote the manuscript. A.L., X.-P.Y., M.J.G. and C.M.T. planned and performed experiments and helped to write the manuscript; L.W. and H.-W.S. interpreted the microarray experiments and ChIP-seq data; H.L.R., W.T.W. and Y.K. performed and interpreted the ChIP-seq data; J.E.K., N.B. and J.R.G. helped to analyse gut lymphocytes; T.S.D. and Q.C. helped to analyse CNS lymphocytes. G.E. provided the Rorc(γt)-_Gfp_TG mice and made helpful suggestions; W.C. provided the _Tgfbr1_f/fCD4-Cre+ mice, contributed to the experimental design and data interpretation; Y.B., E.M.S. and D.J.C. contributed to the experimental design, data interpretation and made helpful suggestions. J.J.O'S. contributed to the experimental design, analysed and interpreted all acquired data and helped to write the manuscript.

Corresponding authors

Correspondence toKamran Ghoreschi or John J. O’Shea.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

PowerPoint slides

Rights and permissions

About this article

Cite this article

Ghoreschi, K., Laurence, A., Yang, XP. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling.Nature 467, 967–971 (2010). https://doi.org/10.1038/nature09447

Download citation

This article is cited by

Editorial Summary

Alternative route to TH17 cells

T-helper 17 (TH17) cells are a subset of T-helper cells that produce interleukin (IL)-17 and are critical for host immunity. IL-6 and transforming growth factor-β (TGF-β) had been thought of as the principal inducers of TH17 differentiation, but this work provides further support for an alternative TGF-β-independent pathway of TH17 cell differentiation in mice. TH17 cells can be generated in the absence of TGF-β signalling by using IL-23 in combination with IL-6 and IL-1β. The resulting TH17 cells express not only RORγ-t, but also T-bet, and are more pathogenic than TH17 cells generated in the presence of TGF-β. These TH17 cells, generated independently of TGF-β, could be potential targets for the treatment of autoimmune disease.