# Recent thymic emigrants preferentially undergo memory inflation after persistent infection

## TL;DR

This study shows that newly produced immune cells from the thymus are preferentially maintained in the memory pool during persistent CMV infection.

## Contribution

The study reveals that recent thymic emigrants, rather than cells produced during latent infection, drive memory inflation in CMV.

## Key findings

- Neonatal CMV exposure expands recent thymic emigrants (RTEs) that are maintained in the memory pool.
- RTEs recruited during infection give rise to effector memory cells, while mature CD8+ T cells become central memory cells.
- Adult exposure to CMV also preferentially recruits RTEs into the effector memory pool.

## 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 produced CD8 + T cells called recent thymic emigrants, or RTEs, which are maintained in the long-lived memory compartment. In contrast, CD8 + T cells produced after the acute phase of infection contribute minimally to memory inflation. We also observed notable phenotypic differences between the RTEs and mature CD8 + T cells that were recruited into the memory inflation response. Whereas the RTEs present at the time of infection gave rise to more effector memory cells, the mature CD8 + T cells 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.

Following 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 that are produced 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 produced 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.