CXXC-finger protein 1 associates with FOXP3 to stabilize homeostasis and suppressive functions of regulatory T cells

FOXP3-expressing regulatory T (T_reg) cells play a pivotal role in maintaining immune homeostasis and tolerance, with their activation being crucial for preventing various inflammatory responses. However, the mechanisms governing the epigenetic program in T_regcells during their dynamic activation remain unclear. In this study, we demonstrate that CXXC finger protein 1 (CXXC1) interacts with the transcription factor FOXP3 and facilitates the regulation of target genes by modulating H3K4me3 deposition.Cxxc1deletion in T_regcells leads to severe inflammatory disease and spontaneous T-cell activation, with impaired immunosuppressive function. As a transcriptional regulator, CXXC1 promotes the expression of key T_regfunctional markers under steady-state conditions, which are essential for the maintenance of T_regcell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of T_regprogram genes in mouse T_regcells, overlapping with FOXP3 binding sites. Given its critical role in T_regcell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.