Functional and Genomic Profiling of Effector CD8 T Cell Subsets with Distinct Fates

An important question in memory T cell differentiation is understanding the mechanisms that regulate the generation of terminal effector cells that die following antigen clearance versus effector cells that give rise to the long‐lived pool of memory CD8 T cells. Using killer cell lectin‐like receptor G1 as a marker to effectively distinguish terminal effectors from memory precursors, we found that despite their diverse cell fates both subsets possess remarkably similar gene expression profiles and function as equally potent direct ex vivo killer cells, with similar ability for inflammatory cytokine production and granzyme B expression. Interestingly, in addition to these conventional effector CTL characteristics memory precursors also produced IL‐2, a property typically ascribed to naïve or memory cells; thus presenting them as a novel effector subset. On the other hand, terminal effector cells represent a “late leaving” subset of cells that continues to perceive stimulation towards the tail end of antigen clearance, and exhibits an enrichment of the “effector cell signature”. Importantly, curtailing stimulation during the later stages of infection enhanced the generation of long‐lived memory cells. Collectively, these data define a model of memory differentiation wherein effector CD8 T cells that are driven further down the differentiation pathway by continued stimulation towards the later stages of infection become metabolically and functionally unfit for memory lineage. These studies strongly support the classical decreasing potential model of memory differentiation, and further demonstrate that “late leaver” effector cells contribute less towards the long‐lived pool of memory CD8 T cells.