CxxC-finger protein 1 regulates Treg fragility associated with H3K4me3 breadth

Foxp3-expressing regulatory T cells (Treg cells) play a central role in maintaining immune homeostasis and tolerance. Activation of Treg cells prevents various types of inflammatory responses. However, it remains unclear how the epigenetic program in Treg cells is maintained during the dynamic activation process. Here we show that Cxxc1 is associated with Foxp3 and positively regulates the expression of target genes at H3K4me3-enriched sites. Treg cell-specific ablation of Cxxc1 in mice resulted in a lethal inflammatory disease characterized by spontaneous T-cell activation. Cxxc1-deficient Treg cells showed reduced immunosuppressive capacity in vivo but also induced aberrant expression of genes associated with Treg fragility. Mechanistically, Cxxc1 promotes the accumulation of H3K4me3 in the broad domain of Ikzf4, suppressing the expression of fragile genes including IFN-γ, and Ikzf4 expression partially restores Treg function.