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.

  • Letter
  • Published:

Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells

Abstract

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs1. The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation2. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (TH17) to T helper type 1 (TH1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the TH17:TH1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the TH17:TH1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when TH17 cells outnumber TH1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of TH17:TH1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: CNS autoimmunity differs in C3H MHC congenic mice.
Figure 2: T cell skewing toward a TH17 or TH1 phenotype directs inflammation to the brain or spinal cord.
Figure 3: IL-17 activity triggered by high TH17:TH1 ratios in the brain is required for parenchymal brain inflammation.
Figure 4: TH17:TH1 ratio of epitope-specific T cells is influenced by functional avidity.

Similar content being viewed by others

References

  1. Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747 (2005).

    Article  CAS  Google Scholar 

  2. Fukazawa, T. et al. Both the HLA-CPB1 and -DRB1 alleles correlate with risk for multiple sclerosis in Japanese: clinical phenotypes and gender as important factors. Tissue Antigens 55, 199–205 (2000).

    Article  CAS  Google Scholar 

  3. Raine, C. The lesion in multiple sclerosis and chronic relapsing experimental allergic encephalomyelitis: a structural comparison. in Multiple Sclerosis: Clinical and Pathogenetic Basis (eds. Raine, C.S., McFarland, H.F. & Tourtellotte, W.W.) 243–286 (Chapman and Hall, London, 1997).

    Google Scholar 

  4. Storch, M.K. et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol. 8, 681–694 (1998).

    Article  CAS  Google Scholar 

  5. Tsunoda, I., Kuang, L.Q., Theil, D.J. & Fujinami, R.S. Antibody association with a novel model for primary progressive multiple sclerosis: induction of relapsing-remitting and progressive forms of EAE in H2s mouse strains. Brain Pathol. 10, 402–418 (2000).

    Article  CAS  Google Scholar 

  6. Muller, D.M., Pender, M.P. & Greer, J.M. A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction. Acta Neuropathol. 100, 174–182 (2000).

    Article  CAS  Google Scholar 

  7. Weissert, R. et al. MHC class II-regulated central nervous system autoaggression and T cell responses in peripheral lymphoid tissues are dissociated in myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis. J. Immunol. 166, 7588–7599 (2001).

    Article  CAS  Google Scholar 

  8. Kjellen, P. et al. The H2-Ab gene influences the severity of experimental allergic encephalomyelitis induced by proteolipoprotein peptide 103–116. J. Neuroimmunol. 120, 25–33 (2001).

    Article  CAS  Google Scholar 

  9. Wensky, A.K. et al. IFN-gamma determines distinct clinical outcomes in autoimmune encephalomyelitis. J. Immunol. 174, 1416–1423 (2005).

    Article  CAS  Google Scholar 

  10. Abromson-Leeman, S. et al. T cell properties determine disease site, clinical presentation and cellular pathology of experimental autoimmune encephalomyelitis. Am. J. Pathol. 165, 1519–1533 (2004).

    Article  CAS  Google Scholar 

  11. Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nat. Med. 13, 139–145 (2007).

    Article  CAS  Google Scholar 

  12. Mendel, I., Kerlero de Rosbo, N. & Ben-Nun, A. A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor Vβ expression of encephalitogenic T cells. Eur. J. Immunol. 25, 1951–1959 (1995).

    Article  CAS  Google Scholar 

  13. Fitzgerald, D.C. et al. Suppressive effect of IL-27 on encephalitogenic TH17 cells and the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 179, 3268–3275 (2007).

    Article  CAS  Google Scholar 

  14. van der Veen, R.C. Nitric oxide and T helper cell immunity. Int. Immunopharmacol. 1, 1491–1500 (2001).

    Article  CAS  Google Scholar 

  15. Cheng, X. et al. The PD-1/PD-L pathway is up-regulated during IL-12–induced suppression of EAE mediated by IFN-γ. J. Neuroimmunol. 185, 75–86 (2007).

    Article  CAS  Google Scholar 

  16. Spanaus, K.S., Schlapbach, R. & Fontana, A. TNF-α and IFN-γ render microglia sensitive to Fas ligand–induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL. Eur. J. Immunol. 28, 4398–4408 (1998).

    Article  CAS  Google Scholar 

  17. Badie, B., Schartner, J., Vorpahl, J. & Preston, K. Interferon-γ induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro. Exp. Neurol. 162, 290–296 (2000).

    Article  CAS  Google Scholar 

  18. Muhl, H. & Pfeilschifter, J. Anti-inflammatory properties of pro-inflammatory interferon-γ. Int. Immunopharmacol. 3, 1247–1255 (2003).

    Article  CAS  Google Scholar 

  19. Cruz, A. et al. Cutting edge: IFN-γ regulates the induction and expansion of IL-17–producing CD4 T cells during mycobacterial infection. J. Immunol. 177, 1416–1420 (2006).

    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. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  21. 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 

  22. Yong, V.W., Power, C., Forsyth, P. & Edwards, D.R. Metalloproteinases in biology and pathology of the nervous system. Nat. Rev. Neurosci. 2, 502–511 (2001).

    Article  CAS  Google Scholar 

  23. Agrawal, S. et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J. Exp. Med. 203, 1007–1019 (2006).

    Article  CAS  Google Scholar 

  24. Tester, A.M. et al. LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. PLoS ONE 2, e312 (2007).

    Article  Google Scholar 

  25. Berahovich, R.D. et al. Proteolytic activation of alternative CCR1 ligands in inflammation. J. Immunol. 174, 7341–7351 (2005).

    Article  CAS  Google Scholar 

  26. Toft-Hansen, H., Nuttall, R.K., Edwards, D.R. & Owens, T. Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis. J. Immunol. 173, 5209–5218 (2004).

    Article  CAS  Google Scholar 

  27. Goverman, J. et al. Transgenic mice that express a myelin basic protein–specific T cell receptor develop spontaneous autoimmunity. Cell 72, 551–560 (1993).

    Article  CAS  Google Scholar 

  28. Abdul-Majid, K.B. et al. Screening of several H-2 congenic mouse strains identified H-2(q) mice as highly susceptible to MOG-induced EAE with minimal adjuvant requirement. J. Neuroimmunol. 111, 23–33 (2000).

    Article  CAS  Google Scholar 

  29. Stromnes, I.M. & Goverman, J.M. Active induction of experimental allergic encephalomyelitis. Nature Protocols 1, 1810–1819 (2006).

    Article  CAS  Google Scholar 

  30. Brabb, T. et al. In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J. Exp. Med. 192, 871–880 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Levin at ZymoGenetics, Inc. for the IL17RA-Fc protein, H. Simkins and N. Mausolf for technical support and animal husbandry, D. Goverman, L. Kicknosway and R. Rowe for assistance with immunohistochemistry, R. Ransohoff for helpful discussions, T. Brabb, L. Castelli, Q. Ji, H. Simkins and A. Weinmann for critical reading of the manuscript, and B. Teeple for assistance with statistical analyses. This work was supported by the National Multiple Sclerosis Society (RG 3851-A-5 to J.M.G.) and the US National Institutes of Health (AI072737 to J.M.G.) and Public Health Service (T32-CA009537 to I.M.S.).

Author information

Authors and Affiliations

Authors

Contributions

I.M.S. conducted most of the experiments; L.M.C. assisted with the RT-PCR experiments and data analyses; D.L. assisted with the evaluation of the histochemical analyses; R.A.H. provided rMOG production protocol and helpful discussions; I.M.S. and J.M.G. designed the study, analyzed the data and wrote the manuscript; and J.M.G. secured the funding.

Corresponding author

Correspondence to Joan M Goverman.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1 and 2 (PDF 332 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stromnes, I., Cerretti, L., Liggitt, D. et al. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med 14, 337–342 (2008). https://doi.org/10.1038/nm1715

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1715

This article is cited by

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