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

The 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.

Superior Adhesion of a Multifunctional Protein-Based Micropatch to Intestinal Tissue by Harnessing the Hydrophobic Effect.

Drug delivery systems comprising drug carriers capable of adhering to intestinal tissue have considerable potential to realize more sophisticated systemic drug delivery and topical drug treatments in the intestinal tract. The development of innovative strategies for improving the adhesion efficiency of carriers is of high importance for the advancement of this field. Herein, a novel approach to achieving high adhesion efficiency of drug carriers is presented, where the accessibility of the carrier to the intestinal surface and its subsequent adhesion to the intestinal tissue are promoted by utilizing the thermodynamic tendency of the hydrophobic carrier and its dispersion solvent, triacetin, to be excluded from the aqueous environment. Drug carriers are fabricated using proteins, imparting multiple functions, including drug release and the removal of reactive oxygen species (ROS). Results of ex vivo studies indicate that this multifunctional protein-based carrier, "protein micropatch," adheres to various mouse intestinal tissues, including the small intestine, colon, and inflamed colon, with high efficiency. Furthermore, protein micropatches, administered to mice via oral or rectal routes, successfully adhere to the intestinal tract. This approach and the highly functionalized carrier described in the study have the potential to significantly contribute to the development of bioadhesive carrier-based drug delivery systems.