Respiratory syncytial virus inhibits type I interferon signaling to maintain HLA-DM expression in CD1c+ dendritic cells.

Respiratory syncytial virus (RSV) infection often elicits ineffective long-term immune responses due to inefficient immune priming, complicating disease management and vaccine development. Dendritic cells (DCs) are central regulators of antiviral immunity and antigen presentation; yet, the direct impact of RSV on these pathways remains poorly understood. In this study, we identify sustained HLA-DM expression as a unique hallmark of RSV infected CD1c+ DCs, a phenotype not observed following influenza infection or poly(I:C) stimulation. Using single cell RNA sequencing, pharmacological inhibition, and complementary controls, we demonstrate that TBK1 dependent Type I Interferon signaling is a key regulator of HLA-DM expression during DC maturation. Co-culture experiments further suggest that HLA-DM-high DCs influence CD4+ T cell differentiation, supporting a model in which sustained HLA-DM expression reshapes antigen presentation and downstream adaptive immunity. Together, these findings uncover a previously unknown link between innate antiviral signaling and antigen presentation machinery in human DCs.