Heightened protection from infectious disease as conferred by vaccination or pathogen exposure relies on the generation and preservation of specific immunological memory. An essential component of most antiviral and many antibacterial immune responses is the generation of pathogen-specific CD8+T cell immunity. Following resolution of acute disease, specific CD8+ effector T cells are subject to a process that combines the selection of defined effector T cell subsets with their gradual maturation and culminates in the establishment of specific CD8+T cell memory. The preservation of specific CD8+T cell memory is integral to the capacity to curtail secondary infections, minimize clinical disease and avert potential death of infected hosts. However, the mechanisms operative in the maintenance of pathogen-specific CD8T cell memory remain incompletely understood. Numerous factors such as persisting antigen, cross-reactive pathogens, non-specific inflammatory alterations and age-associated processes can continuously remodel established CD8+T cell memory and potentially compromise protection of the immunized host. In our recent work on long-term, antiviral CD8+T cell memory, we have found that the transition from effector to memory T cells takes far longer than previously appreciated. Although antiviral CD8+T cell memory established approximately 6 weeks after initial infection exhibits the hallmarks of mature T cell memory, we observed an extended phenotypic and functional maturation process that lasts up to approximately1 year. Surprisingly, aged CD8+ memory T cells appear poised to provide better protection than young CD8+ memory T cells. This research proposal is designed to systematically define the molecular basis of the progressive maturation of established antiviral CD8+T cell memory and to test the hypothesis that aging may, to a certain extent, improve secondary T cell immunity. We expect that these studies will provide essential clues about the nature, scope and physiological limitations of pathogen-specific CD8+T cell memory. The notion that aged CD8+TM with defined phenotypic and functional features can provide enhanced protection will provide an important basis for our conceptualization of T cell memory as well as for prophylactic and therapeutic interventions under clinically relevant conditions such as infectious diseases, neoplastic disease, utoimmunity and transplantation.
