Epigenetic control of the foxp3 locus in regulatory T cells. Regulatory T cells (Tregs) are crucial for maintaining self-tolerance in the immune system by suppressing autoimmunity and excessive immune responses. The transcription factor Foxp3 is essential for Treg development and function, and its expression is tightly regulated. Recent studies show that epigenetic modifications, such as DNA methylation and histone modifications, play a critical role in stabilizing Foxp3 expression and ensuring the long-term identity of Tregs. The foxp3 locus contains an evolutionarily conserved region upstream of exon-1 that is completely demethylated in Foxp3+ CD25+ CD4+ Tregs but methylated in naive CD4+ T cells. This demethylation is associated with histone acetylation and trimethylation of histone H3 at lysine 4, indicating an open chromatin structure in Tregs. In contrast, conventional CD4+ T cells exhibit a more condensed chromatin structure. These epigenetic changes are essential for the stable expression of Foxp3 and the development of a long-term suppressor cell lineage. TGF-β-induced Tregs, which are generated in vitro, show partial demethylation of the foxp3 locus but lack the stable Foxp3 expression and suppressive function seen in naturally occurring Tregs. Upon restimulation in the absence of TGF-β, these TGF-β-induced Tregs lose Foxp3 expression and suppressive activity, highlighting the importance of epigenetic modifications in maintaining Treg stability. The findings suggest that complete demethylation of the foxp3 locus is necessary for the long-term expression of Foxp3 and the establishment of a stable Treg lineage. This has significant implications for therapeutic applications involving Treg induction or transfer, as well as for understanding long-term cell lineage decisions. Epigenetic regulation of the foxp3 locus appears to be a key mechanism in the development and maintenance of Tregs, providing a potential target for therapeutic interventions in autoimmune and inflammatory diseases.Epigenetic control of the foxp3 locus in regulatory T cells. Regulatory T cells (Tregs) are crucial for maintaining self-tolerance in the immune system by suppressing autoimmunity and excessive immune responses. The transcription factor Foxp3 is essential for Treg development and function, and its expression is tightly regulated. Recent studies show that epigenetic modifications, such as DNA methylation and histone modifications, play a critical role in stabilizing Foxp3 expression and ensuring the long-term identity of Tregs. The foxp3 locus contains an evolutionarily conserved region upstream of exon-1 that is completely demethylated in Foxp3+ CD25+ CD4+ Tregs but methylated in naive CD4+ T cells. This demethylation is associated with histone acetylation and trimethylation of histone H3 at lysine 4, indicating an open chromatin structure in Tregs. In contrast, conventional CD4+ T cells exhibit a more condensed chromatin structure. These epigenetic changes are essential for the stable expression of Foxp3 and the development of a long-term suppressor cell lineage. TGF-β-induced Tregs, which are generated in vitro, show partial demethylation of the foxp3 locus but lack the stable Foxp3 expression and suppressive function seen in naturally occurring Tregs. Upon restimulation in the absence of TGF-β, these TGF-β-induced Tregs lose Foxp3 expression and suppressive activity, highlighting the importance of epigenetic modifications in maintaining Treg stability. The findings suggest that complete demethylation of the foxp3 locus is necessary for the long-term expression of Foxp3 and the establishment of a stable Treg lineage. This has significant implications for therapeutic applications involving Treg induction or transfer, as well as for understanding long-term cell lineage decisions. Epigenetic regulation of the foxp3 locus appears to be a key mechanism in the development and maintenance of Tregs, providing a potential target for therapeutic interventions in autoimmune and inflammatory diseases.