Letter | Published:

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

Naturevolume 441pages235238 (2006) | Download Citation

Subjects

Abstract

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (TH) cells are traditionally thought to differentiate into TH1 and TH2 cell subsets. TH1 cells are necessary to clear intracellular pathogens and TH2 cells are important for clearing extracellular organisms1,2. Recently, a subset of interleukin (IL)-17-producing T (TH17) cells distinct from TH1 or TH2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury3,4,5. In contrast, CD4+CD25+Foxp3+ regulatory T (Treg) cells inhibit autoimmunity and protect against tissue injury6. Transforming growth factor-β (TGF-β) is a critical differentiation factor for the generation of Treg cells7. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation8,9, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of TH17 cells. Instead, IL-6 and TGF-β together induce the differentiation of pathogenic TH17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989)

  2. 2

    Bottomly, K. A functional dichotomy in CD4+ T lymphocytes. Immunol. Today 9, 268–274 (1988)

  3. 3

    Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005)

  4. 4

    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)

  5. 5

    Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005)

  6. 6

    Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004)

  7. 7

    Chen, W. et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003)

  8. 8

    Hirano, T. Interleukin 6 and its receptor: ten years later. Int. Rev. Immunol. 16, 249–284 (1998)

  9. 9

    Ozato, K., Tsujimura, H. & Tamura, T. Toll-like receptor signaling and regulation of cytokine gene expression in the immune system. Biotechniques 33 (Suppl.), S66–S68 (2002)

  10. 10

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003)

  11. 11

    Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003)

  12. 12

    Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003)

  13. 13

    Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003)

  14. 14

    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)

  15. 15

    Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002)

  16. 16

    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)

  17. 17

    Gorelik, L. & Flavell, R. A. Transforming growth factor-β in T-cell biology. Nature Rev. Immunol. 2, 46–53 (2002)

  18. 18

    Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992)

  19. 19

    Nardelli, D. T. et al. Association of CD4+ CD25+ T cells with prevention of severe destructive arthritis in Borrelia burgdorferi-vaccinated and challenged gamma interferon-deficient mice treated with anti-interleukin-17 antibody. Clin. Diagn. Lab. Immunol. 11, 1075–1084 (2004)

  20. 20

    Samoilova, E. B., Horton, J. L., Hilliard, B., Liu, T. S. & Chen, Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161, 6480–6486 (1998)

  21. 21

    Okuda, Y. et al. IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte glucoprotein 35–55 induced experimental autoimmune encephalomyelitis. J. Neuroimmunol. 101, 188–196 (1999)

  22. 22

    Okuda, Y., Sakoda, S., Saeki, Y., Kishimoto, T. & Yanagihara, T. Enhancement of Th2 response in IL-6-deficient mice immunized with myelin oligodendrocyte glycoprotein. J. Neuroimmunol. 105, 120–123 (2000)

  23. 23

    Eugster, H. P. et al. Superantigen overcomes resistance of IL-6-deficient mice towards MOG-induced EAE by a TNFR1 controlled pathway. Eur. J. Immunol. 31, 2302–2312 (2001)

Download references

Acknowledgements

We thank R. A. Sobel for histological analysis of CNS tissues from mice, D. Kozoriz for cell sorting, and A. Jäger for technical assistance. This work was supported by grants from the National Multiple Sclerosis Society, the National Institutes of Health, JDRF Center for Immunological Tolerance at Harvard and the Deutsche Forschungsgemeinschaft.

Author information

Author notes

  1. Estelle Bettelli, Yijun Carrier and Wenda Gao: *These authors contributed equally to this work

Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital

    • Estelle Bettelli
    • , Yijun Carrier
    • , Thomas Korn
    • , Howard L. Weiner
    •  & Vijay K. Kuchroo
  2. Transplant Research Center, Beth Israel Hospital, Harvard Medical School, Boston, 77 Avenue Louis Pasteur, Massachusetts, 02115, USA

    • Wenda Gao
    •  & Terry B. Strom
  3. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, 65 Landsdowne Street, Massachusetts, 02139, USA

    • Mohamed Oukka

Authors

  1. Search for Estelle Bettelli in:

  2. Search for Yijun Carrier in:

  3. Search for Wenda Gao in:

  4. Search for Thomas Korn in:

  5. Search for Terry B. Strom in:

  6. Search for Mohamed Oukka in:

  7. Search for Howard L. Weiner in:

  8. Search for Vijay K. Kuchroo in:

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mohamed Oukka or Vijay K. Kuchroo.

Supplementary information

  1. Supplementary Figure 1

    Induction of Th-IL-17 cells by activation of naive CD4+ T cells with plate bound anti-CD3 plus anti-CD28 in the presence of TGF-β and IL-6. (PDF 462 kb)

  2. Supplementary Figure 2

    IL-6 deficient mice are resistant to the development of EAE and fail to generate Th-IL-17 cells. (PDF 520 kb)

  3. Supplementary Figure Legends

    Text to accompany the above Supplementary Figures (DOC 20 kb)

  4. Supplementary Table 1

    Histological Analysis of the CNS from 2D2 and 2D2xTg TGF-b with EAE (XLS 17 kb)

  5. Supplementary Methods

    This file contains additional details on the methods used in this study. (DOC 30 kb)

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/nature04753

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.