Peri-weaning, diet-induced activation of an IFNγ-mediated regulatory circuit promotes cDC1 maturation and CD8+ T Cells differentiation

Maintaining a balanced immunity between pathogen defense and allergen tolerance in neonates is essential for survival and the establishment of life-long immune homeostasis. Instructed by environmental signals, type 1 conventional dendritic cells (cDC1) contribute to both processes but how the balance may be achieved is unclear. Here we uncover an interferon (IFN)γ-driven regulatory circuit in early life that relays dietary cues to spleen cDC1. Loss-of-function demonstrates that IFNγ-mediated STAT1 signaling induces an immunogenic maturation program in spleen cDC1 that instructs cDC1 to expand effector memory CD8⁺ T cells. This cDC1 program emerges during weaning when IFNγ production from lymphocytes rises, occurs in germ-free mice, and remains operative to dietary intervention in adult mice. During the transition from breastfeeding to solid food at weaning, this IFNγ signal relays dietary information to spleen cDC1 to shape the effector phenotype of food antigen- specific CD8+ T cells in a feedforward manner, allowing cDC1 to recalibrate the T cell pool at the time of weaning.