Developmental Origin Governs CD8+ T Cell Fate Decisions during Infection

Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8+ T cell pool that are distinguished by their developmental origin, unique transcriptional profiles, distinct chromatin landscapes, and different kinetics and phenotypes after microbial challenge. These data demonstrate that the naive CD8+ T cell pool is not as homogeneous as previously thought and offers a new framework for explaining the remarkable heterogeneity in the effector and memory T cell subsets that arise after infection. [Display omitted] •Fate mapping reveals developmental layers in the CD8+ T cell response to infection•The fetal layer of CD8+ T cells exhibits rapid and innate-like functions in adults•The adult layer of CD8+ T cells preferentially gives rise to long-lived memory cells•CD8+ T cells with different developmental origins possess distinct regulomes The discovery of multiple sub-populations of naive T cells, distinguished by their developmental origin and molecular profiles prior to microbial challenge, explains the heterogeneity observed in memory and effector pools.