Beyond Conventional Transcriptional Regulation Function: FOXP3 as an Integrative Hub for Chromatin Interactions and Protein Complexes in Immune Regulation

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.