Broomfield et al. demonstrate that early type I interferon blockade alters CXCR3 chemokine regulation and cell location to promote an antigen-dependent CD8+ T cell transition of precursor of exhausted T cells to stem cell–like memory CD8+ T cells for enhanced protection following viral infection and mRNA–lipid nanoparticle vaccination. This evidence concerns the gene CXCR3 and viral infectious disease.