Foxp3によるT細胞の制御性T細胞へのリプログラミング機構を解明

～Foxp3は生体内環境に応じてT細胞を再プログラムし、制御性T細胞のエピゲノムと機能を形成する～

2026-05-07 東京大学

Foxp3 導入によるTregの分子プログラムと機能の形成

＜関連情報＞

• https://www.u-tokyo.ac.jp/focus/ja/press/z0111_00065.html
• https://www.u-tokyo.ac.jp/content/400287311.pdf
• https://www.science.org/doi/10.1126/sciimmunol.aed2111

Foxp3は、制御性T細胞の分子的なアイデンティティと機能を規定する、状況依存的なエピジェネティックプログラムを促進する Foxp3 drives context-dependent epigenetic programs that define regulatory T cell molecular identity and function

Yuxi Wei, Hinako Ago, Ryuichi Murakami, Shotaro Funatsu, […] , and Shohei Hori
Science Immunology  Published:1 May 2026
DOI:https://doi.org/10.1126/sciimmunol.aed2111

Editor’s summary

Regulatory T (T_reg) cells are key orchestrators of immunological tolerance and are controlled by the transcription factor Foxp3. However, whether Foxp3 expression alone is sufficient to confer full T_reg cell identity remains unclear. Using adoptive transfer of Foxp3-transduced conventional T cells into lymphopenic mice, Wei et al. found that a subset of cells acquired T_reg cell–like transcriptional, chromatin, and suppressive features, which required induction of endogenous Foxp3 expression. Acquisition of endogenous Foxp3 occurred in vivo but not in vitro because of elevated AKT-mTOR activity and depended on Foxp3-mediated engagement of STAT5 and NF-κB. These findings support a model in which Foxp3 integrates both intrinsic and environmental cues to confer T_reg cell identity and function. —Claire Olingy

Abstract

Regulatory T cells (T_reg cells) express the master regulator, Foxp3, and display distinctive epigenetic landscapes ensuring T_reg 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, T_reg cell–like transcriptomic and chromatin features, and suppressive functions exclusively in vivo. These Foxp3-driven features were conserved in T_reg cells but impaired in Foxp3-mutant T_reg-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 T_reg 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 T_reg cell identities and functions, with implications for Foxp3-based therapies.