Recent thymic emigrants are preferentially recruited into the memory pool during persistent infection

Abstract

Cytomegalovirus (CMV) leads to a unique phenomenon known as memory inflation, where antigen-specific memory CD8+ T cells continue to accumulate in the peripheral tissues during the latent stage of infection. However, it is still not clear how the inflating pool of memory CD8+ T cells is generated and maintained. In this study, we used murine cytomegalovirus (MCMV) as a model of persistent infection and fate-mapping mice to determine the dynamics of CD8+ T cell recruitment into the memory pool. We found that neonatal exposure to CMV leads to an expansion of newly made CD8+ T cells (recent thymic emigrants, RTEs), which are maintained in the long-lived memory compartment. In contrast, CD8+ T cells made during the latent phase of infection (mature CD8+ T cells) contribute little to the memory pool. We also observed notable phenotypic differences between RTEs and mature cells. Whereas RTEs present at the time of infection gave rise to more effector memory cells, the cells produced later in infection were biased towards becoming central memory cells. Importantly, the preferential recruitment of RTEs into the effector memory pool also occurs during adult exposure to CMV. Collectively, these data demonstrate that persistent infection expands the RTE population, and timing of infection dictates whether neonatal or adult RTEs are locked in to the memory pool. Author SummaryFollowing infection with CMV, CD8+ T cells accumulate in the blood and peripheral organs over time, a feature termed memory inflation. However, it is not clear whether memory inflation is due to the continuous recruitment of cells made during the latent stage of infection or expansion of CD8+ T cells that were present at the time of infection. To address this question, we used a fate-mapping mouse model and examined the recruitment of CD8+ T cells that were produced during different stages of infection. Surprisingly, we discovered that CD8+ T cells exported from the thymus just prior to infection are preferentially recruited and maintained in the memory pool. In contrast, CD8+ T cells made during the latent stage contribute minimally to the inflating pool and exhibit a less differentiated phenotype. These results provide a new conceptual framework for understanding how the memory pool is generated and maintained after persistent viral infection.