Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis
Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis
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DOI：
10.1038/nm.3085
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发表时间：
2013-03-01
期刊：
影响因子：
82.9
通讯作者：
Zhang, Jingwu Z.
中科院分区：
文献类型：
--
作者：
Nie, Hong;Zheng, Yingxia;Zhang, Jingwu Z.
调节性T（T-reg）细胞抑制自身免疫性疾病，受损的T-reg细胞功能与类风湿性关节炎有关。在这里，我们证明，叉头框P3（FOXP 3）的转录活性，因此，T-reg细胞抑制功能的调节在C-末端DNA结合域Ser 418磷酸化。在类风湿性关节炎衍生的T-reg细胞中，Ser 418位点被蛋白磷酸酶1（PP 1）特异性地去磷酸化，其表达和酶活性在发炎的滑膜中由肿瘤坏死因子α（TNF-α）诱导，导致T-reg细胞功能受损。此外，TNF-α诱导的T-reg细胞功能障碍与类风湿性关节炎炎症滑膜中白细胞介素-17（IL-17）（+）和干扰素-γ（IFN-γ）（+）CD 4（+）T细胞数量增加相关。用INF-α特异性抗体治疗恢复了类风湿性关节炎受试者的T-reg细胞功能，这与T-reg细胞中PP 1表达降低和FOXP 3磷酸化增加有关。因此，TNF-α通过FOXP 3去磷酸化控制类风湿性关节炎个体滑膜中T-reg细胞与致病性T（H）17和T（H）1细胞之间的平衡。
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 alpha (TNF-alpha), leading to impaired T-reg cell function. Moreover, TNF-alpha-induced T-reg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-gamma (IFN-gamma)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a INF-alpha-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-alpha 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.