Nat Med：上海免疫所研究者发现英夫利西单抗通过FOXP3磷酸化修复RA患者受损的Treg细胞功能

英夫利西单抗通过FOXP3磷酸化修复RA患者受损的Treg细胞功能

调节性T细胞（Treg）可以抑制免疫反应，而Treg细胞功能受损与类风湿关节炎发病相关。肿瘤坏死因子α与Treg细胞的功能是否存在相关性？来自上海免疫研究所的研究者证明，TNF-α通过FOXP3脱磷酸化调节类风湿关节炎滑膜Treg细胞和致病的TH17及TH1细胞之间的平衡。研究结果在线发表在2013年2月的《自然-医学》（Nature medcine）杂志上。
叉头样转录因子P3（FOXP3）的转录活性及相关的Treg细胞抑制功能是由Ser418的C末端DNA结合域磷酸化调节的。在类风湿关节炎来源的Treg细胞中，蛋白磷酸酶1（PP1）在Ser418位点发生特异性脱磷酸反应；肿瘤坏死因子α（TNF-α）因诱导炎性滑膜中的这种表达及酶活性而使Treg细胞功能受损。而且，TNF-α诱导的Treg细胞功能异常与类风湿关节炎的炎性滑膜中白介素-17（IL-17）、干扰素-γ（IFN-γ）及阳性T细胞数量增多相关。
在类风湿关节炎中，应用TNF-α特异性抗体进行治疗可以通过抑制PP1表达和增加FOXP3转录来修复受损的Treg细胞功能。因此，TNF-α通过FOXP3脱磷酸化调节类风湿关节炎滑膜Treg细胞和致病的TH17及TH1细胞之间的平衡，但这种调节作用的效果因人而异。

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