(A) Summary of the infection protocol eliciting CNS disease; viral distribution is denoted by color. (B) Mechanistic interpretation. In neonates and in adults, a substantial fraction of the rLCMV/INDG i.c. inoculum reaches the systemic circulation (38). Viral infection of secondary lymphoid organs is abortive due to efficient type I IFN–dependent control, whereas CNS infection is productive. In neonates but not in adults, viral gene expression in secondary lymphoid organs coincides with reduced T cell responsiveness. Hence adult mice mount a protective virus-specific (NP396 and other epitopes) CD8⁺ T cell response that clears rLCMV/INDG from the CNS, while virus persists in the neonate’s neurons. The antiviral CD8⁺ T cell response in neonates is inefficient, but ARM infection 50 days later triggers a vigorous response of NP396-specific CTLs (epitope shared by rLCMV/INDG and ARM) that causes CNS disease when reaching persistently rLCMV/INDG-infected neurons. Adult primary rLCMV/INDG infection has been cleared from the CNS, and hence only neonatally rLCMV/INDG-infected mice develop disease.