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

Publication Type	Preprint
Authors	Hu W, Dolsten G, Beroshvili G, Wang E, Wang Z, Ghelani A, Uhl L, Bou Puerto R, Huang X, Michaels A, Hoyos B, Jin W, Pritykin Y, Rudensky A
Journal	Res Sq
Date Published	05/14/2025
ISSN	2693-5015
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.
DOI	10.21203/rs.3.rs-6596747/v1
PubMed ID	40470210
PubMed Central ID	PMC12136213