Romance of the three kingdoms: RORgammat allies with HIF1alpha against FoxP3 in regulating T cell metabolism and differentiation

Abstract

Regulatory T (Treg) cells play an essential role in immune homeostasis by controlling the function of various immune effector cells, including RAR-related orphan receptor gammat⁺ (RORγt⁺) T helper 17 (Th17) cells. Foekhead box P₃ (FoxP₃) is the master regulator of Treg cell function, while RORγt is the key transcription factor for the induction of the interleukin (IL)-17 family of cytokines during Th17 cell differentiation. FoxP3 can directly interact with and negatively regulate the function of RORγt, to determine the balance between induced Treg (iTreg) and Th17 cell polarization. Two recent independent studies from the Pan and Chi Labs have shown how hypoxia-inducible factor 1 alpha (HIF1α) is able to tip the balance of T cell differentiation toward the Th17 lineage by responding to the local changes in metabolic shift or an increase in proinflammatory mediators in the microenvironment. By allying with HIF1α, RORγt wins the fight against FoxP3 and Treg cell commitment.