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Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease

Nature Immunology volume 7, pages 1151–1156 (2006)Cite this article

Abstract

It is unclear whether TGF-β, a critical differentiation factor for T cells producing interleukin 17 (TH-17 cells), is required for the initiation of experimental autoimmune encephalomyelitis (EAE) in vivo. Here we show that mice whose T cells cannot respond to TGF-β signaling lack TH-17 cells and do not develop EAE despite the presence of T helper cell type 1 infiltrates in the spinal cord. Local but not systemic antibody blockade of TGF-β prevented TH-17 cell differentiation and the onset of EAE. The pathogen stimulus zymosan, like mycobacterium, induced TH-17 cells and initiated EAE, but the disease was transient and correlated with reduced production of interleukin 23. These data show that TGF-β is essential for the initiation of EAE and suggest that disease progression may require ongoing chronic inflammation and production of interleukin 23.

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Figure 1: Naive CD4 T cells from CD4dnTGFβRII mice do not generate TH-17 cells.
Figure 2: Mycobacteria stimulate TH-17 cell differentiation without added TGF-β1.
Figure 3: Blockade of TGF-β signaling and local but not systemic anti-TGFβ treatment prevent the development of EAE.
Figure 4: Zymosan induces TH-17 cells and the initiation of EAE but cannot sustain disease progression.

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References

  1. 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 

  2. Billiau, A. & Matthys, P. Modes of action of Freund's adjuvants in experimental models of autoimmune diseases. J. Leukoc. Biol. 70, 849–860 (2001).

    CAS  PubMed  Google Scholar 

  3. Ferber, I.A. et al. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).

    CAS  PubMed  Google Scholar 

  4. Willenborg, D.O., Fordham, S.A., Staykova, M.A., Ramshaw, I.A. & Cowden, W.B. IFN-γ is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide. J. Immunol. 163, 5278–5286 (1999).

    CAS  PubMed  Google Scholar 

  5. Becher, B., Durell, B.G. & Noelle, R.J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110, 493–497 (2002).

    Article  CAS  Google Scholar 

  6. Gran, B. et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J. Immunol. 169, 7104–7110 (2002).

    Article  CAS  Google Scholar 

  7. Zhang, G.X. et al. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-β2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J. Immunol. 170, 2153–2160 (2003).

    Article  CAS  Google Scholar 

  8. Gutcher, I., Urich, E., Wolter, K., Prinz, M. & Becher, B. Interleukin 18-dependent engagement of interleukin 18 receptor-α is required for autoimmune inflammation. Nat. Immunol. 7, 946–953 (2006).

    Article  CAS  Google Scholar 

  9. 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 

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

    Article  CAS  Google Scholar 

  11. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

    Article  CAS  Google Scholar 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. Infante-Duarte, C., Horton, H.F., Byrne, M.C. & Kamradt, T. Microbial lipopeptides induce the production of IL-17 in Th cells. J. Immunol. 165, 6107–6115 (2000).

    Article  CAS  Google Scholar 

  17. Khader, S.A. et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-γ responses if IL-12p70 is available. J. Immunol. 175, 788–795 (2005).

    Article  CAS  Google Scholar 

  18. Massague, J. The transforming growth factor-β family. Annu. Rev. Cell Biol. 6, 597–641 (1990).

    Article  CAS  Google Scholar 

  19. Wahl, S.M., Allen, J.B., Costa, G.L., Wong, H.L. & Dasch, J.R. Reversal of acute and chronic synovial inflammation by anti-transforming growth factor β. J. Exp. Med. 177, 225–230 (1993).

    Article  CAS  Google Scholar 

  20. Wahl, S.M. Transforming growth factor β: the good, the bad, and the ugly. J. Exp. Med. 180, 1587–1590 (1994).

    Article  CAS  Google Scholar 

  21. Zhang, X. et al. Recovery from experimental allergic encephalomyelitis is TGF-β dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int. Immunol. 18, 495–503 (2006).

    Article  CAS  Google Scholar 

  22. Szczepanik, M., Tutaj, M., Bryniarski, K. & Dittel, B.N. Epicutaneously induced TGF-β-dependent tolerance inhibits experimental autoimmune encephalomyelitis. J. Neuroimmunol. 164, 105–114 (2005).

    Article  CAS  Google Scholar 

  23. Murano, M. et al. Latent TGF-β1-transduced CD4+ T cells suppress the progression of allergic encephalomyelitis. J. Leukoc. Biol. 79, 140–146 (2006).

    Article  CAS  Google Scholar 

  24. Cautain, B. et al. Essential role of TGF-β in the natural resistance to experimental allergic encephalomyelitis in rats. Eur. J. Immunol. 31, 1132–1140 (2001).

    Article  CAS  Google Scholar 

  25. Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).

    Article  CAS  Google Scholar 

  26. Yoshitomi, H. et al. A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med. 201, 949–960 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. 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  CAS  Google Scholar 

  29. Chen, Y. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116, 1317–1326 (2006).

    Article  CAS  Google Scholar 

  30. Fontenot, J.D., Rasmussen, J.P., Gavin, M.A. & Rudensky, A.Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

    Article  CAS  Google Scholar 

  31. Zamvil, S. et al. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 317, 355–358 (1985).

    Article  CAS  Google Scholar 

  32. Martin, R., McFarland, H.F. & McFarlin, D.E. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 10, 153–187 (1992).

    Article  CAS  Google Scholar 

  33. Smith, S.B. & Waksman, B.H. Passive transfer and labelling studies on the cell infiltrate in experimental allergic encephalomyelitis. J. Pathol. 99, 237–244 (1969).

    Article  CAS  Google Scholar 

  34. Lafaille, J.J. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev. 9, 139–151 (1998).

    Article  CAS  Google Scholar 

  35. 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).

    CAS  PubMed  Google Scholar 

  36. Gijbels, K., Brocke, S., Abrams, J.S. & Steinman, L. Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. Mol. Med. 1, 795–805 (1995).

    Article  CAS  Google Scholar 

  37. Fossiez, F. et al. Interleukin-17. Int. Rev. Immunol. 16, 541–551 (1998).

    Article  CAS  Google Scholar 

  38. Powell, M.B. et al. Lymphotoxin and tumor necrosis factor-α production by myelin basic protein-specific T cell clones correlates with encephalitogenicity. Int. Immunol. 2, 539–544 (1990).

    Article  CAS  Google Scholar 

  39. Baker, D. et al. Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins. Eur. J. Immunol. 24, 2040–2048 (1994).

    Article  CAS  Google Scholar 

  40. Jovanovic, D.V. et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α, by human macrophages. J. Immunol. 160, 3513–3521 (1998).

    CAS  PubMed  Google Scholar 

  41. Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).

    Article  CAS  Google Scholar 

  42. Jansson, M., Panoutsakopoulou, V., Baker, J., Klein, L. & Cantor, H. Cutting edge: attenuated experimental autoimmune encephalomyelitis in eta-1/osteopontin-deficient mice. J. Immunol. 168, 2096–2099 (2002).

    Article  CAS  Google Scholar 

  43. Ashkar, S. et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287, 860–864 (2000).

    Article  CAS  Google Scholar 

  44. Abel, B., Freigang, S., Bachmann, M.F., Boschert, U. & Kopf, M. Osteopontin is not required for the development of Th1 responses and viral immunity. J. Immunol. 175, 6006–6013 (2005).

    Article  CAS  Google Scholar 

  45. da Silva, A.P. et al. Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-α expression and non-programmed cell death. J. Cell. Physiol. 208, 629–639 (2006).

    Article  Google Scholar 

  46. Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

    Article  CAS  Google Scholar 

  47. Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).

    Article  CAS  Google Scholar 

  48. Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

    Article  CAS  Google Scholar 

  49. McKenzie, B.S., Kastelein, R.A. & Cua, D.J. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 27, 17–23 (2006).

    Article  CAS  Google Scholar 

  50. Gantner, B.N., Simmons, R.M., Canavera, S.J., Akira, S. & Underhill, D.M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003).

    Article  CAS  Google Scholar 

  51. Dillon, S. et al. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J. Clin. Invest. 116, 916–928 (2006).

    Article  CAS  Google Scholar 

  52. Du, Z. et al. Selective regulation of IL-10 signaling and function by zymosan. J. Immunol. 176, 4785–4792 (2006).

    Article  CAS  Google Scholar 

  53. Riley, L.W. Of mice, men, and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis. J. Clin. Invest. 116, 1475–1478 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank F. Powrie (Sir William Dunn School of Pathology, University of Oxford, Oxford, UK) for the transfer of CD4dnTGFβRII breeder mice; H. Jani for initial help in preparation of spinal cords; and H. Boyes for assessing clinical scores in treated mice.

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Authors and Affiliations

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

    Marc Veldhoen, Richard J Hocking, Richard A Flavell & Brigitta Stockinger

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  1. Marc Veldhoen
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  2. Richard J Hocking
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  4. Brigitta Stockinger
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Contributions

M.V. did the experiments; R.J.H. assisted with RT-PCR; R.A.F. provided the CD4dnTGFβ RII mice; and B.S. wrote the paper.

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Correspondence to Brigitta Stockinger.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Cytokine mRNA induction after DC stimulation. (PDF 87 kb)

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Veldhoen, M., Hocking, R., Flavell, R. et al. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7, 1151–1156 (2006). https://doi.org/10.1038/ni1391

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