Ikzf1 association with Foxp3 for Foxp3-dependent gene repression in Treg cells: induction of autoimmunity and tumor immunity by disrupting the association

Abstract

The 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 of IkE5 up-regulated the genes, including Ifng, 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.