Periweaning diet-induced activation of an IFNγ-mediated regulatory circuit promotes the homeostasis of cytotoxic CD8+ T Cells

Balancing pathogen defence with maintaining tolerance to environmental antigens, such as food or commensals, in neonates is essential for survival and the establishment of life-long immune homeostasis. Instructed by environmental signals type 1 conventional dendritic cells (cDC1) drive either T cell tolerance or immunity. 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 program emerges during weaning, when IFNγ production from lymphocytes rises, it occurs in germ-free mice and remains responsive to dietary intervention in adult mice. During the transition from breastfeeding to solid food at weaning, this circuit relays dietary information to spleen cDC1 to shape the effector phenotype of food-antigen specific CD8+ T cells in a feed-forward manner, allowing cDC1 to recalibrate the T cell pool at the moment of nutritional independence.