FoxO-dependent regulation of diacylglycerol kinase α gene expression.

Diacylglycerol kinase α (DGKα) regulates diacylglycerol levels, catalyzing its conversion into phosphatidic acid. The α isoform is central to immune response regulation; it downmodulates Ras-dependent pathways and is necessary for establishment of the unresponsive state termed anergy. DGKα functions are regulated in part at the transcriptional level although the mechanisms involved remain poorly understood. Here, we analyzed the 5' end structure of the mouse DGKα gene and detected three binding sites for forkhead box O (FoxO) transcription factors, whose function was confirmed using luciferase reporter constructs. FoxO1 and FoxO3 bound to the 5' regulatory region of DGKα in quiescent T cells, as well as after interleukin-2 (IL-2) withdrawal in activated T cells. FoxO binding to this region was lost after complete T cell activation or IL-2 addition, events that correlated with FoxO phosphorylation and a sustained decrease in DGKα gene expression. These data strongly support a role for FoxO proteins in promoting high DGKα levels and indicate a mechanism by which DGKα function is downregulated during productive T cell responses. Our study establishes a basis for a causal relationship between DGKα downregulation, IL-2, and anergy avoidance.