# Temporal and Context-Dependent Requirements for the Transcription Factor Foxp3 Expression in Regulatory T Cells

## TL;DR

This study shows that the protein Foxp3 is crucial for regulatory T cells at different stages, especially in tumors, where its absence limits tumor growth.

## Contribution

A novel chemogenetic system reveals stage-specific and context-dependent roles of Foxp3 in regulatory T cells.

## Key findings

- Foxp3 is essential for establishing Treg transcriptional programs in progenitor and newly formed Treg cells.
- Degradation of Foxp3 in mature Treg cells causes minimal transcriptional changes but preserves function.
- Tumoral Treg cells uniquely depend on Foxp3 for suppressive function and tumor growth.

## Abstract

Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of the immune responsiveness. While Foxp3 essential role in Treg l differentiation is well established, the mechanisms by which Foxp3 governs the Treg-specific transcriptional network remain incompletely understood. Here, we employed a novel chemogenetic system of inducible, time-controlled degradation of Foxp3 protein in vivo to dissect its Treg stage stage-specific functions. While Foxp3 was indispensable for the establishment of the Treg transcriptional program and suppressive function during thymic Treg progenitors and newly generated peripheral Treg cells, degradation of Foxp3 in mature Treg cells resulted in unexpectedly minimal transcriptional changes largely limited to direct Foxp3 targets and largely preserved suppressive capacity. However, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impaired suppressive function and tumor growth restraint absent pronounced adverse effects. These studies demonstrate context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs.