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(reg) cells 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. Cxxc1 deletion in T(reg) cells 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(reg) functional markers under steady-state conditions, which are essential for the maintenance of T(reg) cell homeostasis and their suppressive functions. Epigenetically, CXXC1 binds to the genomic regulatory regions of T(reg) program genes in mouse T(reg) cells, overlapping with FOXP3-binding sites. Given its critical role in T(reg) cell homeostasis, CXXC1 presents itself as a promising therapeutic target for autoimmune diseases.