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.