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

• Published in: Nature medicine Vol. 19; no. 3; pp. 322 - 328
• Main Authors: Nie, Hong, Zheng, Yingxia, Li, Runsheng, Guo, Taylor B, He, Dongyi, Fang, Lei, Liu, Xuebin, Xiao, Lianbo, Chen, Xi, Wan, Bing, Chin, Y Eugene, Zhang, Jingwu Z
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2013; Nature Publishing Group
• Subjects: 631/250/127/1220; 631/250/1619/554/1898/1271; 631/250/249/1313/498; 631/250/516; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Biomedicine; Cancer Research; Cells, Cultured; DNA-Binding Proteins - metabolism; Forkhead Transcription Factors - chemistry; Forkhead Transcription Factors - metabolism; Genetic aspects; Health aspects; Humans; Infectious Diseases; Interferon-gamma - biosynthesis; Interleukin-17 - biosynthesis; Interleukin-2 Receptor alpha Subunit - biosynthesis; Interleukin-7 Receptor alpha Subunit - biosynthesis; Metabolic Diseases; Molecular Medicine; Neurosciences; Phosphorylation; Physiological aspects; Protein Phosphatase 1 - metabolism; Rheumatoid arthritis; Risk factors; RNA Interference; RNA, Small Interfering; Synovial Membrane - immunology; Synovial Membrane - metabolism; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; China
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3085

TNF-α suppresses regulatory T (T reg ) cell function, however the mechanism remains unclear. Here Jingwu Z Zhang and colleagues find that in activated T cells, phosphorylation of FOXP3 promotes its transcriptional activity. TNF-α induces protein phosphatase 1 expression, leading to dephosphorylation of FOXP3 and inhibition of T reg cell function. In individuals with rheumatoid arthritis, TNF-α–specific antibody treatment restores T reg cell activity and FOXP3 phosphorylation, suggesting that post-translational modifications, including phosphorylation, regulate FOXP3 activity and T reg cell–mediated suppression. Regulatory T (T reg ) cells suppress autoimmune disease, and impaired T reg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, T reg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis–derived T reg 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 T reg cell function. Moreover, TNF-α–induced T reg 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 T reg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in T reg cells. Thus, TNF-α controls the balance between T reg cells and pathogenic T H 17 and T H 1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.