Foxp3

FOXP3 is a transcription factor of the forkhead/winged-helix family encoded by the FOXP3 gene on the X chromosome. It serves as the master regulator of regulatory T cells (Tregs), which are essential for maintaining peripheral tolerance and preventing autoimmunity. Genetic mutations or dysfunction of FOXP3 cause severe immune dysregulation, most notably the IPEX syndrome in humans and the scurfy phenotype in mice.

The FOXP3 protein contains a forkhead DNA-binding domain at its C-terminus and additional regulatory regions that enable transcriptional activation or repression. It can form dimers and interact with other transcription factors such as NFAT and Runx1 to control a broad program of target genes. The stability of FOXP3 expression in committed Tregs is reinforced by epigenetic mechanisms, including demethylation of the Treg-specific demethylated region (TSDR) within the FOXP3 locus.

In regulatory T cells, FOXP3 promotes the expression of genes associated with suppression, including CTLA4 and IL2RA (CD25), while repressing pro-inflammatory effector programs. It also influences metabolic pathways and cytokine environments that support the suppressive phenotype. FOXP3 activity can be modulated by signaling cues from the immune system, contributing to the dynamic regulation of tolerance.

Clinically, FOXP3 mutations cause IPEX syndrome, characterized by immune dysregulation, enteropathy, endocrinopathies, and dermatitis in affected males. Beyond rare genetic disorders, altered FOXP3 expression or Treg function is investigated in autoimmunity, allergy, infection, and cancer, where increased Treg activity can impact disease outcomes and responses to therapy. FOXP3 remains a key marker for human regulatory T cells in research and diagnostics.