Deletion of a distal IRF4 element prevents inflammation-induced reprogramming of human regulatory T cell fate

Regulatory T (T_reg) cells in mice can lose lineage identity and acquire proinflammatory functions, but whether human T_reg cells are similarly susceptible to cytokine-driven destabilization remains unclear. Here we established an in vitro model of human T_reg cell destabilization defined by silencing of the lineage-specifying transcription factor FOXP3, loss of suppressive function and acquisition of proinflammatory activity. Single-cell chromatin accessibility and transcriptomic profiling revealed a genome-wide increase in accessibility at AP-1-binding sites, including a putative regulatory element distal to IRF4. Increased accessibility at this element correlated with increased IRF4 expression during T_reg cell destabilization, and its excision conferred resistance to inflammatory cytokine-induced reprogramming. Conversely, forced expression of IRF4 together with BATF promoted T_reg cell destabilization. These data identify a distal IRF4 regulatory element as a critical node enabling heightened AP-1-IRF4 cooperative activity to drive T_reg cell destabilization, with implications for the design of more stable and effective T_reg cell-based therapies.