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.

Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand

Abstract

T-helper cells that produce interleukin-17 (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases1,2,3. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type4,5,6,7. Here we present SR1001, a high-affinity synthetic ligand—the first in a new class of compound—that is specific to both RORα and RORγt and which inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors’ transcriptional activity. SR1001 inhibited the development of murine TH17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically TH17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.

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: SR1001 is a selective RORα and RORγ inverse agonist.
Figure 2: SR1001 modulates the expression of ROR target genes by decreasing co-activator recruitment.
Figure 3: SR1001 inhibits the expression of cytokines expressed by T H 17 cells.
Figure 4: SR1001 inhibits T H 17 cell development and IL-17A secretion.

References

  1. McGeachy, M. J. & Cua, D. J. Th17 cell differentiation: The long and winding road. Immunity 28, 445–453 (2008)

    Article  CAS  Google Scholar 

  2. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K. Induction and effector functions of TH17 cells. Nature 453, 1051–1057 (2008)

    Article  ADS  CAS  Google Scholar 

  3. Littman, D. R. & Rudensky, A. Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010)

    Article  CAS  Google Scholar 

  4. Yang, X. X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008)

    Article  CAS  Google Scholar 

  5. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006)

    Article  CAS  Google Scholar 

  6. Ivanov, I. I., Zhou, L. & Littman, D. R. Transcriptional regulation of Th17 cell differentiation. Semin. Immunol. 19, 409–417 (2007)

    Article  CAS  Google Scholar 

  7. Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nature Immunol. 9, 641–649 (2008)

    Article  CAS  Google Scholar 

  8. Kumar, N. et al. The benzenesulfonamide T0901317 is a novel RORα/γ inverse agonist. Mol. Pharmacol. 77, 228–236 (2010)

    Article  CAS  Google Scholar 

  9. Zhang, F. P., Meng, G. X. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nature Immunol. 9, 1297–1306 (2008)

    Article  CAS  Google Scholar 

  10. Ichiyama, K. et al. Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. J. Biol. Chem. 283, 17003–17008 (2008)

    Article  CAS  Google Scholar 

  11. Wang, Y. et al. Modulation of retinoic acid receptor-related orphan receptor α and γ activity by 7-oxygenated sterol ligands. J. Biol. Chem. 285, 5013–5025 (2010)

    Article  CAS  Google Scholar 

  12. Chopra, A. R. et al. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke’s disease. Science 322, 1395–1399 (2008)

    Article  ADS  CAS  Google Scholar 

  13. Jin, L. H. et al. Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORγ. Mol. Endocrinol. 24, 923–929 (2010)

    Article  CAS  Google Scholar 

  14. Xu, J., Wagoner, G., Douglas, J. C. & Drew, P. D. Liver X receptor agonist regulation of Th17 lympocyte function in autoimmunity. J. Leukoc. Biol. 86, 401–409 (2009)

    Article  CAS  Google Scholar 

  15. Xu, J. H., Racke, M. K. & Drew, P. D. Peroxisome proliferator-activated receptor-α agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis. J. Neurochem. 103, 1801–1810 (2007)

    Article  CAS  Google Scholar 

  16. Delerive, P., Chin, W. W. & Suen, C. S. Identification of Reverbα as a novel RORα target gene. J. Biol. Chem. 277, 35013–35018 (2002)

    Article  CAS  Google Scholar 

  17. Wada, T. et al. Identification of oxysterol 7α-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor α (RORα) (NR1F1) target gene and a functional cross-talk between RORα and liver X receptor (NR1H3). Mol. Pharmacol. 73, 891–899 (2008)

    Article  CAS  Google Scholar 

  18. Wang, J., Yin, L. & Lazar, M. A. The orphan nuclear receptor Rev-erbα regulates circadian expression of plasminogen activator inhibitor type 1. J. Biol. Chem. 281, 33842–33848 (2006)

    Article  CAS  Google Scholar 

  19. Okamoto, K. et al. IκBζ regulates TH17 development by cooperating with ROR nuclear receptors. Nature 464, 1381–1385 (2010)

    Article  ADS  CAS  Google Scholar 

  20. Raghuram, S. et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ. Nature Struct. Mol. Biol. 14, 1207–1213 (2007)

    Article  CAS  Google Scholar 

  21. Lighvani, A. A. et al. T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells. Proc. Natl Acad. Sci. USA 98, 15137–15142 (2001)

    Article  ADS  CAS  Google Scholar 

  22. Tamauchi, H. et al. Evidence of GATA-3-dependent Th2 commitment during the in vivo immune response. Int. Immunol. 16, 179–187 (2004)

    Article  CAS  Google Scholar 

  23. Chalmers, M. J. et al. Probing protein ligand interactions by automated hydrogen/deuterium exchange mass spectrometry. Anal. Chem. 78, 1005–1014 (2006)

    Article  CAS  Google Scholar 

  24. Pascal, B. D., Chalmers, M. J., Busby, S. A. & Griffin, P. R. H. D. Desktop: An integrated platform for the analysis and visualization of H/D exchange data. J. Am. Soc. Mass Spectrom. 20, 601–610 (2009)

    Article  CAS  Google Scholar 

  25. Zhang, Z. Q. & Smith, D. L. Determination of amide hydrogen-exchange by mass-spectrometry—a new tool for protein-structure elucidation. Protein Sci. 2, 522–531 (1993)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants to T.P.B. (DK080201, DK089984 and MH084512), to L.A.S. (DK088499) and P.R.G. (GM084041) and a grant from the National Multiple Sclerosis Society to P.D.D. (RG389A2/1). Additionally, the efforts of P.R.G. and W.R.R. were supported by the NIH Molecular Library Screening Center Network (MLSCN) grant U54MH074404 (Hugh Rosen, Principal Investigator).

Author information

Authors and Affiliations

Authors

Contributions

P.R.G. and T.P.B. conceived the project. L.A.S., P.R.G. and T.P.B. planned the project. Medicinal chemistry was planned and performed by P.N., T.M.K. and W.R.R. Biochemical and cell based assays were performed by L.A.S., N.K., Y.W., J.L. and M.A.I. Molecular modelling was performed by D.V. and S.C.C. The EAE model was designed and performed by J.X., G.W. and P.D.D. HDX studies were performed by J.L.L. The manuscript was written by L.A.S. and T.P.B.

Corresponding author

Correspondence to Thomas P. Burris.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-9 with legends. (PDF 720 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Solt, L., Kumar, N., Nuhant, P. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491–494 (2011). https://doi.org/10.1038/nature10075

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10075

This article is cited by

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.

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research