TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells

Significance TNF signals via 2 receptors, TNFR1 and TNFR2. Anti-TNF biologics, which block signaling via both receptors, are now being used to treat millions of patients worldwide for immune-mediated inflammatory diseases. This study demonstrates that TNFR2 plays a major role in limiting the severity and duration of arthritis in animal models and that TNFR2 is important for maintaining the functional activity and phenotypic stability of Treg cells, which are major cellular mediators of immune homeostasis. Treg cells express the functionally important transcription factor FoxP3, and we show that TNFR2 is required for preventing DNA methylation at the Foxp3 promoter thereby maintaining its transcriptional activity. This suggests that specific blockade of TNFR1 would be advantageous.