Virtual memory CD8⁺ T cells in aging: heterogeneity, bystander protection, inflammatory potential, and inhibitory regulation.

Aging reshapes the CD8⁺ T cell compartment through contraction of the naïve pool and expansion of memory-phenotype populations, including the progressive accumulation of antigen-inexperienced virtual memory (VM) CD8⁺ T cells. VM CD8⁺ T cells arise in the absence of foreign antigen priming and acquire a memory-like phenotype. In aged hosts, VM CD8⁺ T cells constitute a substantial fraction of the antigen-inexperienced memory-phenotype CD8⁺ T cell pool, and their differentiation is shaped by self-reactivity, homeostatic cytokines, and transcriptional programs linked to IL-15 and EOMES. During aging, VM CD8⁺ T cells accumulate numerically, display altered proliferative responses, retain sensitivity to homeostatic and inflammatory cytokines, and can preserve effector function during infection. These features suggest that VM CD8⁺ T cells may partially compensate for the age-associated loss of naïve CD8⁺ T cells by providing rapid effector-like responses. At the same time, aged VM CD8⁺ T cells appear to comprise heterogeneous subsets, including populations with cytotoxic and inflammatory potential. Emerging evidence suggests that inhibitory receptors may mark distinct VM states during aging, although their functional significance and potential regulatory role remain to be established.