Neonatal CD8+ T cells resist terminal exhaustion during chronic infection [RNAseq_day8]

Chronic viral infections represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections (HIV, HCV), the underlying mechanisms remain poorly understood. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (LCMV clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially become effector cells early in chronic infection when compared to adult CD8+ T cells, and resist commitment to the exhausted differentiation trajectory. Further, neonatal CD8+ T cells are preferentially maintained as stem-like exhausted progenitors rather than terminally exhausted cells during the chronic phase of infection. The altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant, for the neonatal cells protect from viral replication at the cost of early-onset immunopathology. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influences key cell fate decisions during chronic infection. Adult (8-12 weeks old) or neonatal (5-7 days old) P14 transgenic CD8+ T cells were magnetically enriched, then adoptively transferred to congenically-distinct wildtype recipient mice (4,000 of each cell type). 1 day after adoptive transfer, recipient mice were infected with 2e6 PFU LCMV clone 13 systemically. 8 days post-infection, adult or neonatal donor cells were FACS sorted to at least 95% purity and subjected to RNA sequencing.