The study investigates the gene regulatory basis of bystander activation in CD8+ T cells, particularly in neonatal cells. CD8+ T cells are typically known for their adaptive immune responses, but some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone, a phenomenon called bystander activation. The research demonstrates that neonatal CD8+ T cells exhibit robust and diverse bystander activation, which enhances their innate-like protection against unrelated pathogens. Using multi-omics approaches, the study found that neonatal CD8+ T cells can respond to innate cytokines due to their ability to undergo rapid chromatin remodeling, leading to the activation of a distinct set of enhancers and transcription factors typically found in innate-like T cells. The switch between innate and adaptive functions in CD8+ T cells is mediated by changes in the abundance of distinct cell subsets. The findings support the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought. The study also highlights the role of the Bach2/AP-1 axis in specifying CD8+ T cell innateness, with lower Bach2 levels in neonatal cells enabling them to respond more robustly to inflammation. These results provide insights into the development and regulation of innate and adaptive immune responses in CD8+ T cells.The study investigates the gene regulatory basis of bystander activation in CD8+ T cells, particularly in neonatal cells. CD8+ T cells are typically known for their adaptive immune responses, but some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone, a phenomenon called bystander activation. The research demonstrates that neonatal CD8+ T cells exhibit robust and diverse bystander activation, which enhances their innate-like protection against unrelated pathogens. Using multi-omics approaches, the study found that neonatal CD8+ T cells can respond to innate cytokines due to their ability to undergo rapid chromatin remodeling, leading to the activation of a distinct set of enhancers and transcription factors typically found in innate-like T cells. The switch between innate and adaptive functions in CD8+ T cells is mediated by changes in the abundance of distinct cell subsets. The findings support the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought. The study also highlights the role of the Bach2/AP-1 axis in specifying CD8+ T cell innateness, with lower Bach2 levels in neonatal cells enabling them to respond more robustly to inflammation. These results provide insights into the development and regulation of innate and adaptive immune responses in CD8+ T cells.