W158 - Human Neonatal CD8 T Cells Exhibit Rapid, Short-lived Effector Responses and a Unique Transcription Factor Landscape

Abstract Text: Neonates are distinct in their clinical and cellular responses to viral infections, with neonatal CD8 T cells featuring 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. We set out to define the unique response characteristics and underlying transcription factor landscape of human neonatal CD8 T cells, which may be developmentally programmed for rapid responses to limit immunopathology in early life. Here, we report that human naïve CD8 T cells from neonates are poised for rapid effector differentiation, with elevations of KLRG1, KLRB1, FCER1γ, CD226/DNAM1, granzyme K, TNFα, IL-2, and glycolysis compared to naïve CD8 T cells from adults. Further, rapid cell death occurs with or without activation of neonatal CD8 T cells, with improved survival in the presence of IL-2 and IL-7. These features are associated with a unique transcription factor landscape in neonatal CD8 T cells, including high baseline and post-activation expression of Thymocyte selection–associated high-mobility group box (TOX) and Helios (IKZF2). In conclusion, neonatal CD8 T cells have a unique transcription factor landscape associated with rapid differentiation into short-lived effector cells, revealing key nodes of regulation relevant to the distinctive immunobiology of human neonates.