Elucidating Inflammation-induced Cell Fate Decisions in Primary Human Tregs

Abstract Adoptive regulatory T-cell (Treg) therapy is an emerging therapeutic paradigm for promoting immune tolerance in transplant and autoimmune disease settings. Prior investigations demonstrate that murine Tregs can undergo epigenetic reprogramming within chronically inflamed tissue environments, resulting acquisition of proinflammatory functions the capacity to exacerbate damage. Despite ramifications Treg lineage decommitment cell applications, inflammation-induced human fate decisions remain poorly understood. Here, we present a robust vitromodel IL6, IL1β, IL23-driven instability characterized by progressive FOXP3 HELIOS downregulation, FOXP3conserved non-coding sequence (CNS)2 enhancer re-methylation, diminished vitrosuppressive function, elevated cytokine expression. To gain insight into gene networks enabling loss identity, generated single-cell transcriptomic chromatin accessibility profiles primary maintained presence or absence IL23. Unsupervised clustering revealed dysfunctional population with signature consistent “exTreg” conversion, including altered at IFNγ, IL17A, FOXP3CNS2 loci. Inference transcription factor (TF)-associated changes indicated key role E26 transformation-specific (ETS) family members. Ongoing experiments aim identify specific TF modules be targeted better safeguard function stability therapeutics.