Age-Related Decline in Primary CD8⁺ T Cell Responses Is Associated with the Development of Senescence in Virtual Memory CD8⁺ T Cells

Age-associated decreases in primary CD8⁺ T cell responses occur, in part, due to direct effects on naive CD8⁺ T cells to reduce intrinsic functionality, but the precise nature of this defect remains undefined. Aging also causes accumulation of antigen-naive but semi-differentiated “virtual memory” (T_VM) cells, but their contribution to age-related functional decline is unclear. Here, we show that T_VM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (T_N cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged T_VM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population. CD8 T cell responses decline with age, but virtual memory T (T_VM) cells accumulate. Quinn et al. demonstrate that T_VM cells lose the ability to proliferate in response to TCR signals, but not IL-15, with increasing age. Aged T_VM cells express transcriptional and phenotypic markers of senescence, rather than exhaustion.