A PHD in immunosuppression: oxygen-sensing pathways regulate immunosuppressive Tregs.

The oxygen-sensing prolyl hydroxylase domain (PHD) enzymes are key to maintaining tissue homeostasis during hypoxia via their regulation of the expression and activity of HIF, the master transcription factor for the hypoxic response. In this issue of the JCI, Yamamoto, Hester, and colleagues show that temporal and reversible inhibition of PHD2 in vivo leads to systemic autoimmune disorder. The work demonstrates that a reduction of PHD2 leads to impairment of immunosuppressive Treg cell function via a HIF2α-dependent mechanism, without altering Foxp3 expression. This study indicates that a PHD2/HIF2α axis is critical for maintaining proper Treg function.