Foxp3 drives context-dependent epigenetic programs that define regulatory T cell molecular identity and function

Sci Immunol. 2026 May;11(119):eaed2111. doi: 10.1126/sciimmunol.aed2111. Epub 2026 May 1.

Abstract

Regulatory T cells (Treg cells) express the master regulator, Foxp3, and display distinctive epigenetic landscapes ensuring Treg cell-specific gene expression and stable suppressive functions, yet Foxp3's contribution to this epigenetic identity remains unclear. Leveraging Foxp3-transduced conventional T cells as a gain-of-function probe in mice, we identified a previously unrecognized subset that acquires endogenous Foxp3 expression, Treg cell-like transcriptomic and chromatin features, and suppressive functions exclusively in vivo. These Foxp3-driven features were conserved in Treg cells but impaired in Foxp3-mutant Treg-like cells, demonstrating a Foxp3 requirement. Induction of endogenous Foxp3 expression in vivo required reduced AKT-mTOR signaling and Foxp3-dependent engagement of STAT5 and nuclear factor κB (NF-κB). Temporal chromatin profiling revealed stepwise Foxp3-driven regulatory programs, including a core program shared across Treg cell subsets and effector-specific programs, both associated with NF-κB activity and Foxp3 binding. Thus, Foxp3 integrates cell-intrinsic and environmental contexts to drive epigenetic programs defining Treg cell identities and functions, with implications for Foxp3-based therapies.

MeSH terms

  • Animals
  • Chromatin / metabolism
  • Colitis / immunology
  • Colitis / pathology
  • Epigenesis, Genetic
  • Female
  • Forkhead Transcription Factors* / metabolism
  • Gene Expression Profiling
  • Lymphopenia / immunology
  • Lymphopenia / metabolism
  • Lymphopenia / pathology
  • Male
  • Mice
  • NF-kappa B / metabolism
  • STAT5 Transcription Factor / metabolism
  • T-Lymphocytes, Regulatory* / cytology
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism
  • Transcription, Genetic

Substances

  • Foxp3 protein, mouse
  • Forkhead Transcription Factors
  • STAT5 Transcription Factor
  • NF-kappa B
  • Chromatin