Abstract
SUMMARYThe transcription factor Foxp3 specifically expressed in regulatory T (Treg) cells controls Treg function by repressing some genes and activating others. We have shown here that the transcription factor Ikzf1 associates with Foxp3 via its exon 5 (called IkE5) and that conditional deletion ofIkE5up-regulated the genes, includingIfng, normally repressed by Foxp3 upon TCR stimulation.IkE5-deletion in Treg cells indeed incurred IFN-γ overproduction, which destabilized Foxp3 expression and impaired suppressive function, consequently producing fatal systemic autoimmune diseases and evoking strong anti-tumor immunity. In addition, pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3/Ikzf1/Ikzf3 complex exerted gene-repressing function by competing with epigenetic co-activators, such as p300 and NFAT1, for binding to the target gene loci via chromatin remodeling. Collectively, the association of Ikzf1 with Foxp3 is essential for repressive function of Foxp3, and can be targeted to control autoimmunity and tumor immunity.
Publisher
Cold Spring Harbor Laboratory