Deletion of a Distal IRF4 Element Prevents Inflammation-induced Reprogramming of Human Regulatory T-cell Fate

While preclinical models have demonstrated the remarkable efficacy of Treg cell therapy, lineage-tracing studies have also revealed that murine Tregs can lose lineage identity and adopt a proinflammatory state. Whether human Tregs exhibit a similar susceptibility to inflammatory cytokine-mediated lineage decommitment remains inconclusive.

Here, we present an in vitro model of human Treg destabilization characterized by silencing of the Treg lineage-defining transcription factor, FOXP3, loss of suppressive activity, and gain of proinflammatory functions. Analysis of single-cell ATAC and transcriptomic profiles of Tregs during destabilization revealed a switch in chromatin accessibility between two elements at the IRF4 locus. Excision of the distal IRF4 element enabled Tregs to resist inflammatory cytokine-induced reprogramming, presenting a cell-engineering strategy to design more effective Treg therapies.