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Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis

Nature Medicine volume 19, pages 322–328 (2013)Cite this article

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Abstract

Regulatory T (Treg) cells suppress autoimmune disease, and impaired Treg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis–derived Treg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor α (TNF-α), leading to impaired Treg cell function. Moreover, TNF-α–induced Treg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)+ and interferon-γ (IFN-γ)+CD4+ T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a TNF-α–specific antibody restored Treg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in Treg cells. Thus, TNF-α controls the balance between Treg cells and pathogenic TH17 and TH1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.

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Figure 1: TNF-α in RA-SF impairs Treg cell function.
Figure 2: Decreased FOXP3 phosphorylation in Treg cells treated with TNF-α or RA-SF.
Figure 3: Phosphorylation of Ser418 modulates FOXP3 activity and Treg cell function.
Figure 4: TNF-α induces PP1 expression and activation in Treg cells.
Figure 5: Effect of PP1 on FOXP3 dephosphorylation and Treg cell function.
Figure 6: Restoration of Treg cell function in subjects with rheumatoid arthritis receiving TNF-α–specific antibody (infliximab) treatment.

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Acknowledgements

This work was partly supported by grants from National Natural Science Foundation of China (81072470) and the Shanghai Municipal Education Commission (J50207).

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Author notes

  1. Jingwu Z Zhang

    Present address: Present address: GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai, China.,

  2. Hong Nie, Yingxia Zheng and Runsheng Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Hong Nie, Yingxia Zheng & Jingwu Z Zhang

  2. Institute of Health Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Runsheng Li, Taylor B Guo, Lei Fang, Xi Chen, Bing Wan, Y Eugene Chin & Jingwu Z Zhang

  3. Department of Medicine, Guanghua Rheumatology Hospital, Shanghai, China

    Dongyi He

  4. GlaxoSmithKline Research and Development Center, Zhangjiang Hi-Tech Park, Pudong, Shanghai, China.,

    Xuebin Liu

  5. Department of Surgery, Guanghua Rheumatology Hospital, Shanghai, China

    Lianbo Xiao

  6. Department of Surgery, Brown University School of Medicine-Rhode Island Hospital, Providence, Rhode Island, USA

    Y Eugene Chin

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Contributions

H.N., Y.Z., R.L. and J.Z.Z. designed and discussed the study. H.N., Y.Z. and R.L. performed the majority of the experiments and analyzed the data. L.F., X.C. and B.W. performed cell culture and retroviral transduction. D.H. and L.X. recruited study participants and provided clinical samples. H.N., Y.Z., R.L., T.B.G., L.F., X.L., Y.E.C. and J.Z.Z. contributed to the writing of the paper. J.Z.Z. supervised the project and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.

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Correspondence to Jingwu Z Zhang.

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Nie, H., Zheng, Y., Li, R. et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med 19, 322–328 (2013). https://doi.org/10.1038/nm.3085

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