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

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.