Using a novel synthetic short tandem nucleotide repeat (STR) fluorescent reporter system (DivisionRecorder), Bresser and Kok et al. showed that during an in vivo pathogen-specific immune response, the CD8+ TCM cell pool proliferated during both the effector phase and after the pathogen clearance phase to expand more than the CD8+ TEFF and TEM cell pools. STR tracing + scRNAseq identified distinct TCM subpopulations expressing either multipotency-associated or effector-associated genes. Multipotency positively associated with relative quiescence of TCM cells, which upon pathogen reinfection, expanded to form the TEFF cell pool to mount recall responses.
Contributed by Paula Hochman
ABSTRACT: Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8(+) memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically 'record' the replicative history of different CD8(+) T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T (T(CM)) cell pool is marked by a higher number of prior divisions than the effector memory T cell pool, owing to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single-cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the T(CM) compartment. Specifically, we demonstrate that lowly divided T(CM) cells display enriched expression of stem-cell-associated genes, exist in a relatively quiescent state, and are superior in eliciting a proliferative recall response upon activation. These data provide the first evidence that a stem-cell-like memory T cell pool that reconstitutes the CD8(+) T cell effector pool upon reinfection is marked by prior quiescence.