TNF disables T_REG-cell function through FOXP3 modification

Regulatory T (T_REG) cells have a crucial role in the prevention of autoimmunity. In rheumatoid arthritis (RA), the immunosuppressive functions of these cells are known to be impaired, but what causes this defect? One answer might be TNF-induced dephosphorylation of the key T_REG-cell transcription factor, FOXP3, according to a recent study published in Nature Medicine.

...can TNF inhibitors restore T_REG-cell function?

The authors of this study first demonstrated that synovial fluid from patients with RA diminishes the suppressive activity of T_REG cells obtained from healthy individuals. Next, using a series of blocking antibodies, they confirmed that TNF was the main factor responsible for this effect, and they set out to explore the underlying mechanisms.

Focusing initially on the role of FOXP3, the investigators found that in vitro activation of T_REG cells results in FOXP3 phosphorylation. This post-translational modification (at a specific residue) was crucial for the full repressive activity of FOXP3, as measured by changes in IL-2 production. Intriguingly, the levels of FOXP3 phosphorylation were lower when the T_REG cells were treated with either TNF or synovial fluid from patients with RA, suggesting that downregulation of FOXP3 phosphorylation mediates the impact of TNF on T_REG cells. With additional in vitro experiments, the authors established that in the presence of high TNF levels, as occur in patients with RA, the expression of the protein phosphatase PP1 is upregulated in T_REG cells through the NFκB pathway. PP1 then dephosphorylates FOXP3, resulting in defective T_REG-cell suppressive activity.

So, can TNF inhibitors restore T_REG-cell function? To find out, the researchers analysed the effects of the TNF-blocking antibody infliximab on T_REG cells in ten patients with RA. Although the numbers of T_REG cells in the patients' peripheral blood did not change, the treatment restored the levels of FOXP3 phosphorylation and PP1 in these cells to values similar to those observed in T_REG cells from healthy individuals. These changes were associated with an improvement in T_REG-cell suppressive activity, together with decreased numbers of effector T cells expressing the proinflammatory cytokines IL-17 and IFNγ. Jingwu Zhang, the lead author of the study, concludes that the results provide “a powerful mechanistic explanation as to why TNF blockers work in RA as a disease-modifying treatment”.