TSLP-Driven Chromatin Remodeling and Trained Systemic Immunity after Neonatal Respiratory Viral Infection

Abstract Our studies have previously shown a role for persistent TSLP production in the lungs of mice after early-life respiratory syncytial virus (RSV) infection that leads to an altered immune phenotype, including accumulation “inflammatory” dendritic cells (DC). This study investigates driving systemic trained immunity DC RSV-infected mice. Bone marrow–derived DCs (BMDC) from at 4 wk postinfection showed enhanced expression costimulatory molecules and cytokines, Tslp, regulate cell function. The adoptive transfer BMDC grown was sufficient exacerbate allergic disease development. addition recombinant during differentiation naive induced similar phenotype as mice, suggesting phenotypic changes. To assess these changes, global transcriptomic characterization TSLPR?/? infected with RSV performed higher upregulation type 1 IFN genes concomitant downregulation inflammatory genes. Assay transposase-accessible chromatin using sequencing analysis demonstrated had parallel gain physical accessibility near loss related pathology, regulatory factor (IRF4) STAT3 predicted top transcription factors binding within differentially accessible regions wild-type. Importantly, show absence signaling, are able mount appropriate IFN–associated antiviral response RSV. In summary, RSV-induced alters structure drive innate activates pathogenic gene programs