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:

TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1

Nature Medicine volume 13, pages 711–718 (2007)Cite this article

Abstract

T-helper type 17 cells (TH17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. TH17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-γ. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-α in retinal cells, suggesting a mechanism by which TH17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-γ and inhibited proliferation of TH17. These findings suggest that TH1 cells may mitigate uveitis by antagonizing the TH17 phenotype through the IFN-γ–mediated induction of IL-27 in target tissue. The finding that IL-2 promotes TH17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of TH17 by IFN-γ and/or IL-27 could be used for the treatment of chronic inflammation.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: TH17 cells are present in human PBMC and are expanded by IL-2 during uveitis and scleritis.
Figure 2: Expression of IL-17 in mouse PBMC, lymph node and retina is temporally correlated with progression of EAU.
Figure 3: IL-27 inhibits the proliferation of uveitogenic T cells and the secretion of IL-17 during EAU.
Figure 4: IL-27 expression in PBMC and retina is temporally correlated with the progression of EAU.
Figure 5: IL-27 is constitutively expressed in the retina and is induced in retinal cells by inflammatory cytokines.
Figure 6: IL-27 inhibits IL-17 expression through a STAT1-dependent mechanism.

Similar content being viewed by others

References

  1. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 16, 779–790 (2002).

    Article  CAS  Google Scholar 

  2. Hunter, C.A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat. Rev. Immunol. 5, 521–531 (2005).

    Article  CAS  Google Scholar 

  3. Trinchieri, G., Pflanz, S. & Kastelein, R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19, 641–644 (2003).

    Article  CAS  Google Scholar 

  4. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    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  CAS  Google Scholar 

  6. Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  Google Scholar 

  7. Cua, D.J. & Kastelein, R.A. TGF-β, a 'double agent' in the immune pathology war. Nat. Immunol. 7, 557–559 (2006).

    Article  CAS  Google Scholar 

  8. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  Google Scholar 

  9. Nussenblatt, R.B. Bench to bedside: new approaches to the immunotherapy of uveitic disease. Int. Rev. Immunol. 21, 273–289 (2002).

    Article  Google Scholar 

  10. Jabs, D.A. et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am. J. Ophthalmol. 130, 492–513 (2000).

    Article  CAS  Google Scholar 

  11. Nussenblatt, R.B. et al. Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial. Proc. Natl. Acad. Sci. USA 22, 7462–7466 (1999).

    Article  Google Scholar 

  12. Becker, M.D., Garman, K., Whitcup, S.M., Planck, S.R. & Rosenbaum, J.T. Inhibition of leukocyte sticking and infiltration, but not rolling, by antibodies to ICAM-1 and LFA-1 in murine endotoxin-induced uveitis. Invest. Ophthalmol. Vis. Sci. 42, 2563–2566 (2001).

    CAS  PubMed  Google Scholar 

  13. Nussenblatt, R.B. Proctor lecture. Experimental autoimmune uveitis: mechanisms of disease and clinical therapeutic indications. Invest. Ophthalmol. Vis. Sci. 32, 3131–3141 (1991).

    CAS  PubMed  Google Scholar 

  14. Crane, I.J. et al. Involvement of CCR5 in the passage of Th1-type cells across the blood-retina barrier in experimental autoimmune uveitis. J. Leukoc. Biol. 79, 435–443 (2006).

    Article  CAS  Google Scholar 

  15. Tarrant, T.K., Silver, P.B., Chan, C.C., Wiggert, B. & Caspi, R.R. Endogenous IL-12 is required for induction and expression of experimental autoimmune uveitis. J. Immunol. 161, 122–127 (1998).

    CAS  PubMed  Google Scholar 

  16. Tarrant, T.K. et al. Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J. Exp. Med. 189, 219–230 (1999).

    Article  CAS  Google Scholar 

  17. Caspi, R.R. et al. Genetic susceptibility to experimental autoimmune uveoretinitis in the rat is associated with an elevated Th1 response. J. Immunol. 157, 2668–2675 (1996).

    CAS  PubMed  Google Scholar 

  18. Cho, M.L. et al. STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J. Immunol. 176, 5652–5661 (2006).

    Article  CAS  Google Scholar 

  19. 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 

  20. 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 

  21. Nakae, S. et al. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl. Acad. Sci. USA 100, 5986–5990 (2003).

    Article  CAS  Google Scholar 

  22. Yu, C.R. et al. Cell proliferation and STAT6 pathways are negatively regulated in T cells by STAT1 and suppressors of cytokine signaling. J. Immunol. 173, 737–746 (2004).

    Article  CAS  Google Scholar 

  23. Egwuagu, C.E. et al. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J. Immunol. 168, 3181–3187 (2002).

    Article  CAS  Google Scholar 

  24. Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article  CAS  Google Scholar 

  25. Takase, H. et al. Induction of suppressors of cytokine signaling (SOCS) in the retina during experimental autoimmune uveitis (EAU): potential neuroprotective role of SOCS proteins. J. Neuroimmunol. 168, 118–127 (2005).

    Article  CAS  Google Scholar 

  26. Caspi, R.R. et al. A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J. Immunol. 140, 1490–1495 (1988).

    CAS  PubMed  Google Scholar 

  27. 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 

  28. Owaki, T. et al. A role for IL-27 in early regulation of Th1 differentiation. J. Immunol. 175, 2191–2200 (2005).

    Article  CAS  Google Scholar 

  29. Villarino, A.V. et al. IL-27 limits IL-2 production during Th1 differentiation. J. Immunol. 176, 237–247 (2006).

    Article  CAS  Google Scholar 

  30. Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat. Immunol. 7, 929–936 (2006).

    Article  CAS  Google Scholar 

  31. Yoshimura, T. et al. Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism. J. Immunol. 177, 5377–5385 (2006).

    Article  CAS  Google Scholar 

  32. 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 

  33. Watford, W.T. et al. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202, 139–156 (2004).

    Article  CAS  Google Scholar 

  34. Villarino, A.V. & Hunter, C.A. Biology of recently discovered cytokines: discerning the pro- and anti-inflammatory properties of interleukin-27. Arthritis Res. Ther. 6, 225–233 (2004).

    Article  CAS  Google Scholar 

  35. Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103, 8137–8142 (2006).

    Article  CAS  Google Scholar 

  36. Tato, C.M., Laurence, A. & O'Shea, J.J. Helper T cell differentiation enters a new era: le roi est mort; vive le roi!. J. Exp. Med. 203, 809–812 (2006).

    Article  CAS  Google Scholar 

  37. Li, J., Gran, B., Zhang, G.X., Rostami, A. & Kamoun, M. IL-27 subunits and its receptor (WSX-1) mRNAs are markedly up-regulated in inflammatory cells in the CNS during experimental autoimmune encephalomyelitis. J. Neurol. Sci. 232, 3–9 (2005).

    Article  CAS  Google Scholar 

  38. Sonobe, Y. et al. Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations. Brain Res. 1040, 202–207 (2005).

    Article  CAS  Google Scholar 

  39. Hamzaoui, K. et al. Cytokine profile in Behcet's disease patients. Relationship with disease activity. Scand. J. Rheumatol. 31, 205–210 (2002).

    Article  Google Scholar 

  40. Saruhan-Direskeneli, G., Yentur, S.P., Akman-Demir, G., Isik, N. & Serdaroglu, P. Cytokines and chemokines in neuro-Behcet's disease compared to multiple sclerosis and other neurological diseases. J. Neuroimmunol. 145, 127–134 (2003).

    Article  CAS  Google Scholar 

  41. Okhravi, N., Odufuwa, B., McCluskey, P. & Lightman, S. Scleritis. Surv. Ophthalmol. 50, 351–363 (2005).

    Article  Google Scholar 

  42. Deuter, C.M., Kotter, I., Gunaydin, I., Zierhut, M. & Stubiger, N. Ocular involvement in Behcet's disease: first 5-year-results for visual development after treatment with interferon alfa-2a. Ophthalmologe 101, 129–134 (2004).

    Article  CAS  Google Scholar 

  43. Calguneri, M. et al. Effects of interferon alpha treatment on the clinical course of refractory Behcet's disease: an open study. Ann. Rheum. Dis. 62, 492–493 (2003).

    Article  CAS  Google Scholar 

  44. Nussenblatt, R.B. et al. Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration. J. Autoimmun. 21, 283–293 (2003).

    Article  CAS  Google Scholar 

  45. Egwuagu, C.E., Yu, C.R., Li, Z. & Nussenblatt, R.B. SOCS5 mRNA levels in peripheral blood mononuclear cells (PBMC): a potential bio-marker for monitoring response of uveitis patients to Daclizumab therapy. J. Autoimmun. 24, 39–46 (2005).

    Article  CAS  Google Scholar 

  46. Hofmann, H., Schulz-key, S., Hertle, D. & Kirsch, M. Orgaotypic cultures of the rat retina. in New Methods for Culturing Cells from Nervous Tissues—Bio Valley Monogr. Vol. 1 (eds. Poindron, P., Piguet, P. & Forster, E.) 58–73 (Karger, Basel, Switzerland, 2005).

    Chapter  Google Scholar 

Download references

Acknowledgements

We thank R. Caspi for reading the manuscript; R. Fariss and J.-Y. Tsai for assistance with confocal microscopy; and D. Levy (New York University) for providing the Stat1−/− and Stat3fl/fl mice. This research was funded by Intramural Research Programs of the National Eye Institute and the US National Institutes of Health.

Author information

Author notes

  1. Ahjoku Amadi-Obi and Cheng-Rong Yu: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ahjoku Amadi-Obi, Cheng-Rong Yu, Xuebin Liu, Rashid M Mahdi, Yun Sang Lee & Charles E Egwuagu

  2. Clinical Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Grace Levy Clarke & Robert B Nussenblatt

  3. Experimental Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Igal Gery

Authors
  1. Ahjoku Amadi-Obi
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Cheng-Rong Yu
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Xuebin Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Rashid M Mahdi
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Grace Levy Clarke
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Robert B Nussenblatt
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Igal Gery
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Yun Sang Lee
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Charles E Egwuagu
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

A.A.-O. and C.-R.Y. conducted all experiments, prepared the figures and assisted with manuscript writing. X.L. assisted with EAU experiments and FACS analysis, and generated the Stat3−/− mice. R.M.M. performed qRT-PCR analyses. G.L.C. and R.B.N. examined patients, obtained clinical specimens and generated clinical data of the patients. I.G. assisted with EAU induction and performed mouse injections of IL-17–specific antibody for EAU inhibition. Y.S.L. conducted the chromatin immunoprecipitation (CHIP) assays. C.E.E. initiated and supervised the project and wrote the manuscript with the editorial assistance of all other authors.

Corresponding author

Correspondence to Charles E Egwuagu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

IL-2 induces the expansion of TH17 cells. (PDF 821 kb)

Supplementary Fig. 2

IFN-γ induces SOCS1 and SOCS3 gene expression in PBMC of patients with scleritis. (PDF 161 kb)

Supplementary Table 1

Summary of the clinical information of patients. (PDF 1185 kb)

Supplementary Methods (PDF 77 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amadi-Obi, A., Yu, CR., Liu, X. et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 13, 711–718 (2007). https://doi.org/10.1038/nm1585

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1585

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