TNF-α Impairs Regulatory T Cells in Patients with Rheumatoid Arthritis

New research elucidates the role of tumor necrosis factor (TNF)–α in immune regulation in patients with rheumatoid arthritis (RA). Hong Nie, MD, PhD, of the Shanghai Jiao Tong University School of Medicine in China, and colleagues examined the synovium of patients with RA in order to better understand the relationship between regulatory T (T_reg) cells and pathogenic T cells. The results were published in Nature Medicine.¹

Previous studies have noted that the number/percentage of T_reg cells does not differ between the synovial fluid of healthy individuals and individuals with RA. Thus, patients with RA have synovial inflammation despite normal levels of T_reg cells.

“This paradox triggered our interest and prompted us to investigate the underlying mechanism. We later discovered that synovial T_reg cells had no regulatory function and that there was a posttranslational defect in FOXP3 (FOXP3 was not properly phosphorylated),” explained Jingwu Z. Zhang, also of the Shanghai Jiao Tong University School of Medicine, by e-mail.

The authors found that TNF-α induces FOXP3 dephosphorylation, thereby controlling the balance of T_reg cells and pathogenic Th17 and Th1 cells. The improper phosphorylation of FOXP3 translates into severely impaired regulatory function.

Thus, aberrant TNF-α production in the synovium drives a pathological circuit by inducing macrophage-produced protein phosphatase 1 (PP1). PP1 then dephosphorylates the Ser418 phosphorylation site of the FOXP3 in T_reg cells.

When the authors treated patients with RA with TNF-α–specific antibody, they were able to restore T_reg cell function. They also found an associated decrease in PP1 expression and increased FOXP3 phosphorylation in T_reg cells.

“This post translational defect of FOXP3/T_reg cells can be corrected by giving TNF-α blockers. The conclusion of the study provides a powerful mechanistic explanation as to why TNF-α works in RA as a disease-modifying treatment,” wrote Dr. Zhang.

Many inflammatory diseases have impaired T_reg cells. It may be that FOXP3 and other transcription factors are influenced and/or impaired by the local proinflammatory cytokine milieu. The transcription factors may be modified at a posttranslational or epigenetic level by the cytokines explained Dr. Zhang.

These results add to previous studies that have demonstrated that protein kinase C-θ (PKC-θ) mediates the inhibitory effects of TNF-α on T_reg cells.

Dr. Pullen is a medical writer based in the Chicago area.

Reference

1. Nie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med. 2013;19:322-328.