Preexisting High Frequencies of Memory CD8⁺ T Cells Favor Rapid Memory Differentiation and Preservation of Proliferative Potential upon Boosting

Memory CD8⁺ Tcell quantity and quality determine protective efficacy against reinfection. Heterologous prime boost vaccination minimizes contraction of anamnestic effectors and maximizes memory CD8⁺ Tcell quantity but reportedly erodes proliferative potential and protective efficacy. This study exploited heterologous prime boost vaccination to discover parameters regulating effector CD8⁺ Tcell contraction and memory differentiation. When abundant memory Tcells were established, boosting induced only 5-8 cell divisions, unusually rapid memory Tcell differentiation as measured by phenotype and mitochondrial bioenergetic function, long-lived survival of 50% of effector Tcells, and preservation of proliferative potential. Conversely, boosting insituations of low memory CD8⁺ Tcell frequencies induced many cell divisions, increased contraction of effector cells, and caused senescence, low mitochondrial membrane potential, and poorly protective memory. Thus, anamnestic memory Tcell differentiation is flexible, and abundant quantity can be achieved while maximizing protective efficacy and preserving proliferative potential.