GSE112176
A Foxp3 mutation drives Th2 effector function in regulatory T cells
Regulatory T (Treg) cells maintain immune tolerance through the action of the master  regulator FOXP3, a transcription factor crucial for Treg cells function and homeostasis.  We identified an IPEX patient with a FOXP3 mutation in the domain swap interface of  the protein (mutant M370I). Recapitulation of this Foxp3 variant in mice led to an autoimmune syndrome  similar to the patient and consistent with an unrestrained Th2 immune response.  Genomic analysis of Treg cells by RNA-seq, Foxp3 ChIP-seq and H3K27ac-HiChIP  revealed a specific de-repression of the T helper type 2 (Th2) transcriptional program  leading to the generation of Th2-like Treg cells that are unable to suppress extrinsic Th2  cells. Th2-like Treg cells are characterized by increased intra-chromosomal interactions  in the Th2 locus leading to type-2 cytokines production. Our research provides cellular  and molecular characterizations of mechanisms used by Foxp3 to restrain Th2 transdifferentiation  and promote optimal Treg suppressive function and stability. Overall design: Wild-type (WT) and mutant M370I (MT) mouse Treg cells were analysed for: gene expression by RNA-seq, Foxp3 binding profile by Foxp3 ChIP-seq and for 3-dimensional genome structure by H3K27ac HiChIP