Novel Foxol-dependent transcriptional programs control T_(reg) cell function

摘要

Regulatory T (T_(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T_(reg) cell homeostasis and function, whereas the early T_(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T_(reg)-cell-commitment stage to control T_(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxol is a pivotal regulator of T_(reg) cell function. T_(reg) cells express high amounts of Foxol and display reduced T-cell-receptor-induced Akt activation, Foxol phosphorylation and Foxol nuclear exclusion. Mice with T_(reg)-cell-specific deletion of Foxol develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T_(reg) cells. Genome-wide analysis of Foxol binding sites reveals ～300 Foxol-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxol signalling module controls a novel genetic program indispensable for T_(reg) cell function.