Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population

Abstract

Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated that circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was terminally fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection. Notably, this terminally differentiated effector memory CD8 T cell population (terminal-Tem)was conflated within the conventional Tempopulation, prompting redefinition of the classical characteristics of Temcells. Murine terminal-Temwere transcriptionally, functionally, and developmentally unique compared to Temcells. Through mass cytometry and single-cell RNA sequencing (RNA-seq) analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-Tempopulation of CD8 T cells that was transcriptionally distinct from Temand Tcm. Key findings from this study show that parsing of terminal-Temfrom conventionally defined Temchallenge the reported characteristics of Tembiology, including enhanced presence in lymphoid tissues, robust IL-2 production, and recall potential, greater than expected homeostatic fitness, refined transcription factor dependencies, and a distinct molecular phenotype. Classification of terminal-Temand clarification of Tembiology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.