Abstract Body

The discovery of the transcription factor Forkhead box-p3 (Foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of T
regulatory (Treg) cells, a cellular population with profound immunoregulatory activities. Work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of Foxp3 in Treg cells. The equilibrium between phenotypic plasticity and stability of Treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate Foxp3 expression. Our studies have suggested that specific modifications of DNA and histones are required for the establishment of the chromatin structure in conventional CD4⁺ T (Tconv) cells for their future differentiation into the Treg cell lineage. These events were accompanied by very early oscillatory changes in Foxp3 chromatin conformation. The identification of the transcriptional and epigenetic determinants governing Foxp3 gene expression and transcription of its splicing variants help to dissect the requirements for the delicate balance between immune tolerance and autoimmunity.