Inducible protein degradation reveals inflammation-dependent function of the Treg cell lineage–defining transcription factor Foxp3

Regulatory T cells (T_reg cells) are immunosuppressive CD4 T cells defined by expression of the transcription factor Foxp3. Genetic loss-of-function mutations in Foxp3 cause lethal multiorgan autoimmune inflammation resulting from defects in T_reg cell development and suppressive activity. Whether T_reg cells are continuously dependent on Foxp3 is still unclear. Here, we leveraged chemically induced protein degradation to show that functionally suppressive T_reg cells in healthy organs can persist in the near-complete absence of Foxp3 protein for at least 10 days. Conversely, T_reg cells responding to type 1 inflammation in settings of autoimmunity, viral infection, or cancer were selectively lost upon Foxp3 protein depletion. Acute degradation experiments revealed that Foxp3 acts mostly as a direct transcriptional repressor and modulates responsiveness to cytokine stimulation. This inflammation-dependent requirement for continuous Foxp3 activity enabled induction of a selective antitumor immune response upon systemic Foxp3 depletion, without causing deleterious T cell expansion in healthy organs.