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

Adoptive regulatory T cell (Treg) therapy is an emergent treatment paradigm for restoring immune tolerance in patients with autoimmune and inflammatory diseases. 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.