IL-6/STAT3 signaling is known to initiate the TH17 differentiation program, but the upstream regulatory mechanisms remain minimally explored. Here, we show that Cxxc finger protein 1 (Cxxc1) promoted the generation of TH17 cells as an epigenetic regulator and prevented their differentiation into Treg cells. Mice with a T cell-specific deletion of Cxxc1 were protected from experimental autoimmune encephalomyelitis and were more susceptible to Citrobacter rodentium infection. Cxxc1 deficiency decreased IL-6Rα expression and impeded IL-6/STAT3 signaling, whereas the overexpression of IL-6Rα could partially reverse the defects in Cxxc1-deficient TH17 cells in vitro and in vivo. Genome-wide occupancy analysis revealed that Cxxc1 bound to Il6rα gene loci by maintaining the appropriate H3K4me3 modification of its promoter. Therefore, these data highlight that Cxxc1 as a key regulator governs the balance between TH17 and Treg cells by controlling the expression of IL-6Rα, which affects IL-6/STAT3 signaling and has an impact on TH17-related autoimmune diseases.
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