%0 Journal Article
%T Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.
%A He M
%A Zong X
%A Xu B
%A Qi W
%A Huang W
%A Djekidel MN
%A Zhang Y
%A Pagala VR
%A Li J
%A Hao X
%A Guy C
%A Bai L
%A Cross R
%A Li C
%A Peng J
%A Feng Y
%J J Exp Med
%V 221
%N 9
%D 2024 Sep 2
%M 38935023
%F 17.579
%R 10.1084/jem.20232068
%X 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.