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.
Bibliographical noteFunding Information:
This work was funded by the National Institutes of Health Director’s New Innovator Award Program DP2-OD-006467 (D.M.), Ruth L. Kirschstein NRSA award AI084622 (KAF) and NIH T32AI007313 (J.M.S.). The authors acknowledge Jon Yewdell and Hao Shen for sharing recombinant pathogens and the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598.