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<p>Regulatory T (T<sub>reg</sub>) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the T<sub>reg</sub> transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated T<sub>reg</sub> cells, Foxp3 loss in mature T<sub>reg</sub> cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature T<sub>reg</sub> cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of T<sub>reg</sub> cell transcriptome and fitness. Furthermore, tumoral T<sub>reg</sub> cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for T<sub>reg</sub> transcriptional and functional programs.</p>

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Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Wei Hu,
  • Gabriel A. Dolsten,
  • Eric Y. Wang,
  • Giorgi Beroshvili,
  • Zhong-Min Wang,
  • Aazam P. Ghelani,
  • Lion F. K. Uhl,
  • Regina Bou-Puerto,
  • Xiao Huang,
  • Anthony J. Michaels,
  • Beatrice E. Hoyos,
  • Wenjie Jin,
  • Yuri Pritykin,
  • Alexander Y. Rudensky

摘要

Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the Treg transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated Treg cells, Foxp3 loss in mature Treg cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature Treg cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of Treg cell transcriptome and fitness. Furthermore, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs.