Epigenetic initiation of the TH17 differentiation program is promoted by Cxxc finger protein 1

IL-6/STAT3 signaling is known to initiate the T(H)17 differentiation program, but the upstream regulatory mechanisms remain minimally explored. Here, we show that Cxxc finger protein 1 (Cxxc1) promoted the generation of T(H)17 cells as an epigenetic regulator and prevented their differentiation into T-reg 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-6R alpha expression and impeded IL-6/STAT3 signaling, whereas the overexpression of IL-6R alpha could partially reverse the defects in Cxxcl-deficient T(H)17 cells in vitro and in vivo. Genome-wide occupancy analysis revealed that Cxxc1 bound to Il6r alpha 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 T(H)17 and T-reg cells by controlling the expression of IL-6R alpha, which affects IL-6/STAT3 signaling and has an impact on T(H)17-related autoimmune diseases.