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.

Microbial exposure during development can elicit long-lasting effects on the health of an individual. However, how microbial exposure in early life leads to permanent changes in the immune system is unknown. Here, we show that the microbial environment alters the set point for immune susceptibility by altering the developmental architecture of the CD8+ T cell compartment. In particular, early microbial exposure results in the preferential expansion of highly responsive fetal-derived CD8+ T cells that persist into adulthood and provide the host with enhanced immune protection against intracellular pathogens. Interestingly, microbial education of fetal-derived CD8+ T cells occurs during thymic development rather than in the periphery and involves the acquisition of a more effector-like epigenetic program. Collectively, our results provide a conceptual framework for understanding how microbial colonization in early life leads to lifelong changes in the immune system.

The immune system is stratified into layers of specialized cells with distinct functions. Recently, Lin28b was shown to serve as a master regulator of fetal lymphopoiesis, programming the development of more innate-like lymphocytes in early life. However, it remains unclear whether Lin28b specifies innate functions in more conventional adaptive lymphocytes. In this report, we discovered that Lin28b promotes the development of a more innate-like lineage of CD8+ T cells that is capable of protecting the host against a wide variety of pathogens in the absence of TCR stimulation. Using RNA-seq and ATAC-seq, we found that Lin28b transcriptionally and epigenetically programs CD8+ T cells to be highly responsive to innate cytokines. We also performed scRNAseq and found that the shift from innate-like CD8+ T cells in early life to adaptive CD8+ T cells in adulthood is mediated by changes in the abundance of distinct subsets of cells. Remarkably, the innate CD8+ T cell subset predominates in early life but is also present in adult mice and humans. Collectively, our findings demonstrate that neonatal CD8+ T cells are a distinct lineage of lymphocytes that provide the host with innate defense in early life.

It is well known that males and females respond differently to intracellular pathogens. Females mount a more robust immune response than males, which decreases their susceptibility to infection but comes at the cost of increasing immunopathology. However, the underlying basis for sex-specific differences in the CD8 + T cell response to infection remains poorly understood. In this study, we show that female CD8 + T cells have an intrinsic propensity to become short-lived effectors, whereas male CD8 + T cells give rise to more memory precursor effector cells after murine infection with either a virus (vaccinia virus) or bacteria ( Listeria monocytogenes) . Interestingly, we found that the propensity of female CD8 + T cells to form short-lived effectors is not because they respond to lower amounts of cognate Ag but rather because they have an enhanced capacity to respond to IL-12, which facilitates more effector cell differentiation at each round of cell division. Our findings provide key insights into the sex-based immunological differences that underlie variations in the susceptibility to infection in males and females. ImmunoHorizons , 2019, 3: 121–132.

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