Early-life human CD8+ T cells exhibit rapid, short-lived effector responses and a unique transcription factor landscape

Neonates and infants are distinct in their clinical and cellular responses to viral infections, with neonatal CD8+ T cells displaying innate-like characteristics and a lower threshold for T cell receptor (TCR) activation relative to adult counterparts. However, specific molecular programs that drive these unique responses are incompletely understood, particularly in humans, and targetable pathways to modulate viral illness in this vulnerable population remain to be elucidated. Early-life immune responses may be developmentally programmed to prioritize protection from tissue immunopathology, especially while protection is conferred by maternal immunoglobulin. We set out to define the unique response characteristics and transcription factor landscape of neonatal human CD8+ T cells. Here, we report evidence that naïve neonatal human CD8+ T cells are poised for an immediate effector switch, with elevations of KLRG1, FCER1G, CD226/DNAM1, granzymes A/K, TNF, IL-2, and glycolysis compared to naïve adult CD8+ T cells. Further, rapid proliferation and cell death occur upon activation of neonatal CD8+ T cells, with cell viability largely rescued by IL-2 or IL-7. These features are coupled with a unique transcription factor landscape, including high baseline and post-activation expression of thymocyte selection–associated high-mobility group box (TOX) and HELIOS (IKZF2). Additionally, we show that these glycolytic, effector and transcription signatures continue in postnatal life until at least two months of age. We conclude that early-life human CD8+ T cells have a unique transcription factor landscape and metabolic state associated with an immediate effector switch and short-lived effector program, revealing key nodes of regulation relevant for the unique immunobiology of neonatal humans.