Replicative history marks transcriptional and functional disparity in the CD8+ T cell memory pool

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 cell (T CM ) pool is marked by a higher number of prior divisions than the effector memory T cell pool, due 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 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.

CD8 memory precursor cell generation is a continuous process

“…This is in agreement with the gradual acquisition of epigenetic modifications that lead to a poised transcriptional state of the effector molecule loci in memory CD8 T cells (Dogra et al, 2016;Henning et al, 2018). Moreover, a recent paper by Bresser et al (Bresser et al, 2022) using an elegant ''division recorder'' accordingly demonstrate that memory cells are derived from cells that have undergone a large number of divisions during the activation/effector phase. They also show that among the TCM pool of memory cells, those that have performed more divisions express more genes associated with effector functions (Bresser et al, 2022).…”

Effect of cellular aging on memory T-cell homeostasis

“…However, these studies have focused on the age of the host rather than the age of the cell, making a comparison of these results and our predictions speculative. Recent studies using the Cre-recombinase technology ( 48 , 53 ) do provide an avenue that could be exploited to delineate the age of the cell from the age of its host. Such dedicated experiments would be required to test the predictions of the cellular aging model.…”

“…Traditionally, models of T-cell homeostasis assume that cells can perform an infinite number of cell divisions, and are bounded only by the resources available at the time ( 29 ). However, a cell’s inherent division and loss rates change over time due to age, differentiation stage and division history ( 48 – 53 ). We, therefore, investigate the role that cellular aging may play in homeostasis and the long-term maintenance of T-cell memory.…”

Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

“…Most recently, Bresser et al developed a method for tracking division number in a population of cells by using a reporter construct with a synthetic short tandem repeat that has a fixed probability for slippage mutations at each division (86). In this system, the number of cell divisions corresponded to the fraction of cells in the population that expressed a fluorescent protein from the reporter construct.…”