H3K27-specific demethylase orchestrates the phenotypic and functional plasticity of intestinal ILC3s

Group 3 innate lymphoid cells (ILC3s) exhibit dynamic plasticity, with their differentiation and function orchestrated by epigenetic mechanisms, including histone modifications and DNA methylation. We identify the histone demethylases UTX and JMJD3 as pivotal regulators of ILC3 specialization. Their deficiency disrupts subset balance: NKp46⁺ ILC3s are depleted with impaired IL-22 production, whereas CCR6⁺ ILC3s expand and exhibit enhanced IL-17A-mediated antifungal immunity. Single-cell profiling reveals that UTX/JMJD3 ablation epigenetically restricts double-negative (DN)-to-NKp46⁺ differentiation while potentiating CCR6⁺ polarization, rewiring ILC3 lineage trajectories through chromatin remodeling. Cleavage under targets and tagmentation (CUT&Tag) analysis demonstrates that UTX directly occupies enhancer regions upstream of Tcf7, where it catalyzes H3K27me3 demethylation to maintain an open chromatin state. Retroviral Tcf7 reconstitution rescues the NKp46⁺ ILC3 deficit and normalizes cytokine production, positioning TCF7 as the key effector downstream of UTX. These findings establish UTX/JMJD3 as central epigenetic gatekeepers of mucosal immunity, offering therapeutic avenues for inflammatory disorders driven by ILC3 dysregulation.