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Abstract
Live-attenuated viruses are key to vaccine strategies, yet mechanisms driving immune responses to replication-deficient strains remain unclear. Using a murine cytomegalovirus (MCMV) model, we examined CD8 T cell responses during replication-deficient infection. Contrary to expectations, replication-deficient MCMV induced a 2–3-fold stronger acute CD8 T cell response and larger memory populations compared to replication-competent infection. Analysis revealed that conventional dendritic cell (cDC) numbers were preserved in replication-deficient infection but declined with viral replication. Reintroduction of type I interferons reduced CD8 T cell expansion and cDC numbers, implicating inflammatory signaling in limiting antigen cross-presentation. These findings identify a mechanism by which replication-deficient MCMV enhances CD8 T cell responses, informing vaccine design strategies.