The fate of CD8+ T cells during infection is linked to their developmental origin

Abstract

Key features of the CD8+ T cell response to infection are the robust clonal expansion and phenotypic diversification of naïve precursors into effector and memory cells. However, mechanisms that regulate the fate of naïve CD8+ T cells after microbial challenge remain a subject of controversy. Previous studies have suggested heterogeneity in the effector pool is driven by differences in TCR avidity, asymmetric cell division, and environmental cues. However, one variable that has not been closely examined is the developmental origin of naïve CD8+ T cells. Notably, the pool of naïve CD8+ T cells in the adult is comprised of clonotypes that were produced during various stages of life. To determine whether the developmental origin of naïve CD8+ T cells in adults plays a deterministic role in their fate after infection, we developed a system to ‘timestamp’ CD8+ T cells from various stages of development (1 day, 1 week, and 4 weeks) and examined their phenotype and behavior in 8 week-old adult mice. Interestingly, we found naïve CD8+ T cells made early in life predominantly display a CD44hi CD122hi memory phenotype whereas cells made later in life are CD44lo CD122lo. In vitro stimulation of stamped populations showed that fetal- and neonatal-derived CD8+ T cells are hypersensitive to IL12/IL18 and proliferate more rapidly than cells made in older animals. In response to infection in adulthood, both polyclonal and monoclonal CD8+ T cells produced in early life skew towards a terminally differentiated short-lived effector phenotype (KLRG1hiCD127lo), indicating this phenomenon is TCR independent. These data indicate that the spectrum of CD8+ T cell differentiation observed after infection is influenced by when the responding cells were initially made.