Antagonism of tumor-necrosis factor (TNF) is an effective treatment for rheumatoid arthritis. In Nature Medicine, Zhang and colleagues show that TNF in the inflamed synovium of patients with rheumatoid arthritis induces dephosphorylation of a serine residue (Ser418) in the DNA-binding domain of the transcription factor Foxp3 and that phosphorylation at this site is required for the inhibitory function of regulatory T cells (Treg cells). The number of Treg cells is normal in the synovial fluid of patients with rheumatoid arthritis, but their suppressive function is impaired. The authors show that TNF induces the upregulation of the phosphatase PP1 in Treg cells, which interacts with Foxp3 and mediates dephosphorylation of Ser418. Treatment of rheumatoid arthritis patients with infliximab (antibody to TNF) restores both Treg cell function and Foxp3 phosphorylation to levels similar to those in healthy subjects.

Nat. Med. (10 February 2013) doi:10.1038/nm.3085