Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity

Highlights•Ikzf1 binds Foxp3 via its exon 5, promoting gene repression with chromatin remodeling•Treg-specific deletion of IkE5 induces severe autoimmunity and anti-tumor immunity•IkE5−/− Treg cells show impaired functional stability due to IFN-γ overexpression•Ikzf1 and Ikzf3 are required for Treg cell homeostasis in mice and humansSummaryThe master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.Graphical abstract