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:

T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis

Nature Medicine volume 16, pages 406–412 (2010)Cite this article

Subjects

Abstract

Interferon-β (IFN-β) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-β in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-β was effective in reducing EAE symptoms induced by T helper type 1 (TH1) cells but exacerbated disease induced by TH17 cells. Effective treatment in TH1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In TH17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-β treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-γ. In the absence of IFN-γ signaling, IFN-β therapy was ineffective in EAE. In RRMS patients, IFN-β nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-β is proinflammatory in TH17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-β.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Effect of IFN-β on mouse TH17 differentiation.
Figure 2: Effects of IFN-β on IFN-γ and IL-10 production in CD4+ T cells.
Figure 3: IFN-β treatment blocks TH1-induced EAE but exacerbates TH17-induced EAE.
Figure 4: IFN-β treatment requires IFN-γ signaling to suppress EAE symptoms.
Figure 5: Effect of IFN-β on human TH differentiation.
Figure 6: Pretreatment cytokine profiles in sera from individuals with multiple sclerosis that do or do not respond to IFN-β.

Similar content being viewed by others

References

  1. Arnason, B.G. Immunologic therapy of multiple sclerosis. Annu. Rev. Med. 50, 291–302 (1999).

    Article  CAS  Google Scholar 

  2. Wang, A.G., Lin, Y.C., Wang, S.J., Tsai, C.P. & Yen, M.Y. Early relapse in multiple sclerosis–associated optic neuritis following the use of interferon β-1a in Chinese patients. Jpn. J. Ophthalmol. 50, 537–542 (2006).

    Article  CAS  Google Scholar 

  3. Benveniste, E.N. & Qin, H. Type I interferons as anti-inflammatory mediators. Sci. STKE 2007, pe70 (2007).

    Article  Google Scholar 

  4. Prinz, M. et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675–686 (2008).

    Article  CAS  Google Scholar 

  5. Guo, B., Chang, E.Y. & Cheng, G. The type I IFN induction pathway constrains TH17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118, 1680–1690 (2008).

    Article  CAS  Google Scholar 

  6. Nagai, T., Devergne, O., van Seventer, G.A. & van Seventer, J.M. Interferon-β mediates opposing effects on interferon-γ–dependent interleukin-12 p70 secretion by human monocyte-derived dendritic cells. Scand. J. Immunol. 65, 107–117 (2007).

    Article  CAS  Google Scholar 

  7. McRae, B.L., Semnani, R.T., Hayes, M.P., van Seventer, G.A. & Type, I. IFNs inhibit human dendritic cell IL-12 production and TH1 cell development. J. Immunol. 160, 4298–4304 (1998).

    CAS  PubMed  Google Scholar 

  8. Martín-Saavedra, F.M., Gonzalez-Garcia, C., Bravo, B. & Ballester, S. β interferon restricts the inflammatory potential of CD4+ cells through the boost of the TH2 phenotype, the inhibition of TH17 response and the prevalence of naturally occurring T regulatory cells. Mol. Immunol. 45, 4008–4019 (2008).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Fitzgerald, D.C. et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27–stimulated T cells. Nat. Immunol. 8, 1372–1379 (2007).

    Article  CAS  Google Scholar 

  11. 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 

  12. Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  Google Scholar 

  13. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).

    Article  CAS  Google Scholar 

  14. 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. Nat. Immunol. 10, 314–324 (2009).

    Article  CAS  Google Scholar 

  15. Platanias, L.C. Mechanisms of type-I- and type-II-interferon–mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005).

    Article  CAS  Google Scholar 

  16. Nguyen, K.B. et al. Interferon α/β–mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox. Nat. Immunol. 1, 70–76 (2000).

    Article  CAS  Google Scholar 

  17. Tanabe, Y. et al. Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-α β responses in T lymphocytes. J. Immunol. 174, 609–613 (2005).

    Article  CAS  Google Scholar 

  18. Wong, L.H., Hatzinisiriou, I., Devenish, R.J. & Ralph, S.J. IFN-γ priming up-regulates IFN-stimulated gene factor 3 (ISGF3) components, augmenting responsiveness of IFN-resistant melanoma cells to type I IFNs. J. Immunol. 160, 5475–5484 (1998).

    CAS  PubMed  Google Scholar 

  19. 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 

  20. Berenson, L.S., Gavrieli, M., Farrar, J.D., Murphy, T.L. & Murphy, K.M. Distinct characteristics of murine STAT4 activation in response to IL-12 and IFN-α. J. Immunol. 177, 5195–5203 (2006).

    Article  CAS  Google Scholar 

  21. Parronchi, P. et al. IL-4 and IFN (α and γ) exert opposite regulatory effects on the development of cytolytic potential by TH1 or TH2 human T cell clones. J. Immunol. 149, 2977–2983 (1992).

    CAS  PubMed  Google Scholar 

  22. 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 

  23. Graber, J.J. et al. Cytokine changes during interferon-β therapy in multiple sclerosis: correlations with interferon dose and MRI response. J. Neuroimmunol. 185, 168–174 (2007).

    Article  CAS  Google Scholar 

  24. Bartosik-Psujek, H. & Stelmasiak, Z. The interleukin-10 levels as a potential indicator of positive response to interferon β treatment of multiple sclerosis patients. Clin. Neurol. Neurosurg. 108, 644–647 (2006).

    Article  Google Scholar 

  25. Awasthi, A. et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007).

    Article  CAS  Google Scholar 

  26. 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 

  27. Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).

    CAS  Google Scholar 

  28. Lucchinetti, C.F. et al. A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain 125, 1450–1461 (2002).

    Article  Google Scholar 

  29. Hengstman, G.J., Wesseling, P., Frenken, C.W. & Jongen, P.J. Neuromyelitis optica with clinical and histopathological involvement of the brain. Mult. Scler. 13, 679–682 (2007).

    Article  CAS  Google Scholar 

  30. Zhang, Z. et al. Interleukin-17 causes neutrophil mediated inflammation in ovalbumin-induced uveitis in DO11.10 mice. Cytokine 46, 79–91 (2009).

    Article  CAS  Google Scholar 

  31. Liang, S.C. et al. An IL-17F/A heterodimer protein is produced by mouse TH17 cells and induces airway neutrophil recruitment. J. Immunol. 179, 7791–7799 (2007).

    Article  CAS  Google Scholar 

  32. Smith, E. et al. IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice. J. Immunol. 179, 8274–8279 (2007).

    Article  CAS  Google Scholar 

  33. Ishizu, T. et al. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain 128, 988–1002 (2005).

    Article  Google Scholar 

  34. Warabi, Y., Matsumoto, Y. & Hayashi, H. Interferon β-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J. Neurol. Sci. 252, 57–61 (2007).

    Article  CAS  Google Scholar 

  35. Shimizu, Y. et al. Development of extensive brain lesions following interferon β therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis. J. Neurol. 255, 305–307 (2008).

    Article  Google Scholar 

  36. Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95, 14863–14868 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank J. Mountz (University of Alabama at Birmingham) for the kind gift of Rebif and Y. Rosenberg-Hasson for running the multiplex cytokine assay. This study was funded by US National Institutes of Health grant R01NS 55997 to L.S., US National Multiple Sclerosis Society grant RG3891-A1, National Institutes of Health grant RO1AI1076562-01 to C.R. and National Multiple Sclerosis Society grant FG 1817-A-1 to R.C.A.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA

    Robert C Axtell, Brigit A de Jong, Roopa Bhat, May Han, Franklin Zhong, Jim G Castellanos, Robert Mair, Athena Christakos, Ilan Kolkowitz, Liat Katz & Lawrence Steinman

  2. Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Brigit A de Jong

  3. Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

    Brigit A de Jong, Laura F van der Voort, Joep Killestein & Chris H Polman

  4. Department of Immunology and Schering-Plough Biopharma, Palo Alto, California, USA

    Katia Boniface & René de Waal Malefyt

  5. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Patrizia De Sarno

  6. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Rodrigo Naves & Chander Raman

Authors
  1. Robert C Axtell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brigit A de Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katia Boniface
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura F van der Voort
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roopa Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patrizia De Sarno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rodrigo Naves
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. May Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Franklin Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jim G Castellanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Robert Mair
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Athena Christakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ilan Kolkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Liat Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Joep Killestein
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Chris H Polman
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. René de Waal Malefyt
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Lawrence Steinman
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Chander Raman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.C.A., L.S. and C.R. discussed, designed and wrote this report; L.S. and C.R. contributed equally as senior authors, and R.C.A. conducted or supervised all experiments. C.H.P., J.K. and L.F.v.d.V. characterized RRMS clinical data and collected serum. B.A.d.J., M.H. and I.K. assisted in analyzing multiplex data from RRMS. P.D., R.N., J.G.C., I.K. and R.M. assisted in EAE experiments. B.A.d.J. and L.K. performed histology on EAE spinal cords. A.C. and F.Z. performed the STAT1 activation assays. R.B., J.G.C. and A.C. assisted with mouse T cell experiments. R.d.W.M. and K.B. performed the human T cell experiments.

Corresponding authors

Correspondence to Lawrence Steinman or Chander Raman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Table 1 and Supplementary Methods (PDF 681 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Axtell, R., de Jong, B., Boniface, K. et al. T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis. Nat Med 16, 406–412 (2010). https://doi.org/10.1038/nm.2110

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2110

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