Age-related dysregulation of CD8+ T cell memory specific for a persistent virus is independent of viral replication

The immune system devotes substantial resources to the lifelong control of persistent pathogens, which were hypothesized to play an important role in immune aging. Specifically, the presence of latent herpesviruses has been correlated with immune exhaustion and shorter lifespan in octogenarians. But neither the causality nor the mechanistic link(s) were established, and the relative roles of persistent antigenic stimulation and of virus-independent homeostatic disturbances in T cell aging remain unresolved. We longitudinally analyzed expansion, contraction, and long-term maintenance of CD8(+) T cells responding to localized infection with a latent virus, HSV-1. Young mice exhibited the expected expansion and contraction of HSV-1-specific cells and the stable maintenance of memory T cells into advanced adulthood. However, upon entry into senescence, many (>40%) animals exhibited an accumulation in Ag-specific cells (memory inflation) which in some animals was comparable to that observed in acute infection. Inflation occurred to the same extent in control mice and mice continuously treated with the anti-HSV drug famciclovir, which inhibits viral replication and was able to reduce expression of the glycoprotein B. Age-related inflation was also found long after infection with an acute virus. The inflating cells largely maintained Ag-specific function, and exhibited typical central memory phenotype, with no signs of Ag-specific activation. They exhibited increased expression of CD122 and CD127, akin to the Ag-independent T cell clonal expansions found in old specific pathogen-free laboratory mice. This collectively suggests that, in this model, the inflating cells may be selected for high responsiveness to environmental cytokines largely in an Ag-independent manner.