Gene regulatory basis of bystander activation in CD8+ T cells (human scRNA-seq)

CD8+ T cells have been categorized as an adaptive lymphocyte, based on their ability to recognize specific foreign antigens and mount memory responses. However, neonatal and adult CD8+ T cells are derived from distinct HSC progenitors, which may alter the roles they play during infection. Here, we demonstrate that neonatal CD8+ T cells can be activated by innate cytokines alone and protect the host from a variety of unrelated pathogens in the absence of TCR signaling. Using a multi-omics approach, we found that neonatal CD8+ T cells are highly responsive to innate cytokines because they can rapidly undergo chromatin remodeling, resulting in the usage of a distinct set of enhancers that are more commonly found in innate-like T cells. We also identified a key gene regulatory axis (Bach2/AP1) that is differentially utilized by neonatal and adult CD8+ T cells to toggle their responsiveness to innate cytokines. Importantly, the developmental switch between innate and adaptive functions in the CD8+ T cell compartment is not mediated by a change in the maturation of individual cells along a linear axis, but rather by changes in the abundance of distinct subsets of cells. Collectively, our findings provide support for the layered immune hypothesis and indicate that the CD8+ T cell compartment is more phenotypically diverse than previously thought.