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 circulating memory cells can be further divided into effector memory (T em ) and central memory (T cm ) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was simultaneously 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-T em ) was conflated within the conventional T em population, prompting redefinition of the classical characteristics of T em cells. Murine terminal-T em were transcriptionally, functionally, and developmentally unique compared to T em cells. Through mass cytometry and single-cell RNAseq analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-T em population of CD8 T cells that was transcriptionally distinct from T em and T cm . A key finding of this study was that parsing of terminal-T em from conventionally defined T em challenges classical characteristics of T em biology, 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-T em and clarification of T em biology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.

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