The function of regulatory T (Treg) cells is known to be impaired in rheumatoid arthritis (RA). In Nature Medicine, Zhang and colleagues delineate the molecular mechanism underlying this impairment. The transcription factor Foxp3 is fundamental to Treg cells' suppressive abilites and for defining their cellular identity; however, certain inflammatory environments can perturb its activity. The authors show that synovial fluid from patients with RA reduced Treg cell activity and anergy and that the inflammatory cytokine TNF was uniquely responsible for this. In patients with RA and in TNF-treated Treg cells, Treg cell frequency and their Foxp3 expression appear normal, but phosphorylation of Foxp3 is reduced. Impairment of Foxp3 activity reduced its ability to repress Treg cells' IL-2 expression. Knockdown and immunoprecipitation show that expression of the phosphatase PP1 is increased by TNF; PP1 associates with Foxp3 and thereby reduces its phosphorylation. TNF blockade in patients with RA reduces PP1, restores Foxp3 phosphorylation and rescues Treg cell suppressive function. These findings suggest another level at which TNF-blockade may ameliorate autoinflammatory disease.

Nat. Med. 19, 322–328 (2013)