{Reference Type}: Journal Article
{Title}: Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.
{Author}: He M;Zong X;Xu B;Qi W;Huang W;Djekidel MN;Zhang Y;Pagala VR;Li J;Hao X;Guy C;Bai L;Cross R;Li C;Peng J;Feng Y;
{Journal}: J Exp Med
{Volume}: 221
{Issue}: 9
{Year}: 2024 Sep 2
{Factor}: 17.579
{DOI}: 10.1084/jem.20232068
{Abstract}: Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.