Lifelong self-renewal and competition shape the virtual memory CD8 T-cell compartment during aging

Primary CD8+ T-cell responses decline with age, increasing susceptibility to novel infections. Virtual memory (VM) CD8+ T cells are memory-phenotype cells that respond rapidly to infection and undergo marked expansion with age. Although aged VM cells exhibit functional impairment, cellular senescence, and clonal expansion, the mechanisms responsible for these changes remain poorly understood. Here, we show that the VM-cell compartment in aged mice is derived predominantly from cells generated early in life and maintained through continuous self-renewal. Over time, resident VM cells acquire increased competitive fitness, resulting in progressive enrichment of the resident population and exclusion of newly generated VM cells. Consequently, unlike the naive CD8+ T-cell compartment, which is continuously replenished throughout life, the VM-cell compartment becomes dominated by long-lived resident cells. Depletion of resident VM cells resets the aged VM-cell compartment and permits expansion of newly generated VM cells. These findings identify lifelong self-renewal and competition as key mechanisms shaping VM-cell aging.