Aging promotes acquisition of naive-like CD8⁺ memory T cell traits and enhanced functionalities

Protective T cell memory is an acquired trait that is contingent upon the preservation of its constituents and therefore vulnerable to the potentially deleterious effects of organismal aging. Here, however, we have found that long-term T cell memory in a natural murine host-pathogen system can substantially improve over time. Comprehensive molecular, phenotypic, and functional profiling of aging antiviral CD8⁺ memory T cells (CD8⁺ T_M) revealed a pervasive remodeling process that promotes the gradual acquisition of distinct molecular signatures, of increasingly homogeneous phenotypes, and of diversified functionalities that combine to confer a CD8⁺ T_M-autonomous capacity for enhanced recall responses and immune protection. Notably, the process of CD8⁺ T_M aging is characterized by a progressive harmonization of memory and naive T cell traits, is broadly amenable to experimental acceleration or retardation, and serves as a constitutional component for the "rebound model" of memory T cell maturation. By casting CD8⁺ T_M populations within the temporal framework of their slowly evolving properties, this model establishes a simple ontogenetic perspective on the principal organization of CD8⁺ T cell memory that may directly inform the development of improved diagnostic, prophylactic, and therapeutic modalities.