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Beyond Conventional Transcriptional Regulation Function: FOXP3 as an Integrative Hub for Chromatin Interactions and Protein Complexes in Immune Regulation
1
State Key Laboratory of Veterinary Public Health and Security, Beijing 100193, China
2
Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, Beijing 100193, China
3
College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
*
Author to whom correspondence should be addressed.
Biology 2026, 15(3), 254; https://doi.org/10.3390/biology15030254
Submission received: 31 December 2025
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Revised: 24 January 2026
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Accepted: 29 January 2026
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Published: 30 January 2026
(This article belongs to the Special Issue Regulation of Gene Expression in Immune Cell Development and Function)
Simple Summary
Regulatory T cells (Tregs), a distinct subset of CD4+ T lymphocytes, play indispensable roles in restraining immune responses to sustain immune tolerance and prevent excessive inflammation. The Forkhead box transcription factor FOXP3 serves as the master regulator for the development and function of regulatory T cells. Understanding how FOXP3 exerts its regulatory functions across various biological settings remains a major research focus. Current findings reveal that FOXP3 interacts with diverse context-dependent cofactors and utilizes its DNA-bridging capacity to mediate long-range chromatin interactions. Thus, FOXP3 represents a novel class of transcription factor that functions as a multimodal interaction hub, integrating diverse signals to dynamically coordinate global gene expression, a paradigm distinct from its previously defined role as a conventional and single-acting transcription factor.
Abstract
As the lineage-defining transcription factor for regulatory T cells (Tregs), FOXP3 plays a critical role in maintaining immune homeostasis. However, FOXP3 has not been found to regulate the expression of immune suppressive cytokines so far, and the specific molecular mechanisms of its function remain an ongoing debate. Emerging evidence reveals that FOXP3 has functions beyond its traditional role as a DNA-binding transcriptional regulator. It possesses unique characteristics distinct from other Forkhead (FKH) family members or lineage-defining transcription factors, including its distinctive sequence recognition preferences, multimeric structure, and function as a central hub for multiprotein complex assembly. Critically, FOXP3 mediates long-range chromatin interactions through its DNA-bridging capacity and multimerization. Furthermore, it integrates environmental signals by interacting with diverse context-dependent cofactors to dynamically regulate gene expression. This review focuses on recent advances elucidating these novel functions of FOXP3, aiming to provide a reference for a deeper understanding of its multifaceted roles in Treg biology.
Keywords:
FOXP3; regulatory T cells; transcription factor; DNA binding
