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.

Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism

“…Because ROCK activity was shown to be increased in SLE and RA patients (13,14), it is possible that the ROCK2-dependent component of the IFN-γ secretion pathway is elevated with RA progression and this is inhibited directly by KD025. In addition, Treg-suppressive activity has been previously shown to be diminished in RA patients (20,38) and may contribute to excessive IFN-γ levels observed in these patients (Fig. S10B).…”

Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

“…Blockade of TNF-α also increases the ratio of T reg to T H 17 cells 37,38 , and it was recently reported that this effect is attributable to the recovery of T reg cell function 38 . These reports suggest that regulating the balance of T reg to T H 17 cells is important for the treatment of RA.…”

Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis

“…It is well known that a substrate molecule with different phosphorylation sites may occupy multipotential states. A recent study from Zhang et al (22) identified Ser 418 of the Foxp3 protein as a potential key phosphorylation site responsible for impaired Treg cell function in rheumatoid arthritis, which is dephosphorylated by PP1 in response to TNF-␣ signaling. Moreover, Morawski et al (40) reported that cyclin-dependent kinase 2 (CDK2) phosphorylates Foxp3 protein and alters its stability and activity and suggested that the cyclin-dependent kinase (CDK) motifs and nearby lysine residues cooperate to form a phosphodegron that regulates Foxp3 phosphorylation-dependent ubiquitination and degradation (22).…”

“…Previous studies showed that deacetylation of Foxp3 is linked to impaired Treg cell function in autoimmune disorders (21), whereas phosphorylation and ubiquitination of Foxp3 affects its activity and Treg cell function (22,23). Furthermore, our previous study suggested that GSK-3␤ (glycogen synthase kinase 3␤) was able to inactivate Foxp3 protein (24).…”