Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells

Regulatory T (T_reg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the T_reg transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated T_reg cells, Foxp3 loss in mature T_reg cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature T_reg cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of T_reg cell transcriptome and fitness. Furthermore, tumoral T_reg cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for T_reg transcriptional and functional programs.