Transcriptional modulation of regulatory T cell development by novel regulators NR4As.

Regulatory T (Treg) cells with high expression of both CD25 and Foxp3 are developed in the thymus and also peripheral tissues. Treg cells suppress the activation and functions of effector T cells raised against specific antigens and are crucial for maintaining immune homeostasis. Treg cell development is associated with the induction of and epigenetic alterations of forkhead transcription factor Foxp3. Foxp3 expression is increased by the activation of several transcription factors including nuclear factor-kappa B (NF-κB), nuclear factor of activated T cells (NFAT), and Smad3 in response to various signals such as TGFβ, retinoic acid, and rapamycin. Recently, the orphan nuclear receptor 4A proteins (NR4As) including NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor1) are reported to regulate Treg cell development through activation of Foxp3 and have therapeutic potentials in treating immune disorders. This review summarizes the function and regulatory mechanisms of Treg cells and also implicates current advances in immunomodulatory functions of NR4As and their therapeutic potentials in inflammation and cancer.