Chemically-induced protein degradation reveals inflammation-dependent requirement for Treg lineage-defining transcription factor FOXP3

Regulatory T (Treg) cells are immunosuppressive CD4 T cells defined by expression of the transcription factor FOXP3. Genetic loss-of-function mutations in Foxp3 cause lethal multi-organ autoimmune inflammation resulting from defects in Treg cell development and suppressive activity. Whether FOXP3 is continuously required to maintain existing Treg cells is still unclear, however. Here, we leveraged chemically-induced protein degradation to show that functionally suppressive Treg cells in healthy organs can persist in the near-complete absence of FOXP3 protein for at least 10 days. Conversely, Treg 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 as a direct transcriptional repressor to modulate responsiveness to cytokine stimulation. This inflammation-dependent requirement for FOXP3 enabled induction of a selective anti-tumor immune response upon systemic FOXP3 depletion, without causing deleterious T cell expansion in healthy organs.