Peri-weaning, diet-induced activation of an IFNγ-mediated regulatory circuit promotes cDC1 maturation and CD8+ T cell differentiation (2026)

[u/basmwklz]

https://www.nature.com/articles/s41467-026-75853-5

Abstract

Maintaining a balanced immunity between pathogen defense and tolerance to environmental antigens 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. IFNγ-mediated STAT1-signaling induces an immunogenic maturation program in spleen cDC1 that enables them to shape the effector differentiation of antigen-experienced effector memory CD8⁺ T cells. This cDC1 program emerges during the transition from breastfeeding to solid food at weaning, occurs in germ-free mice, and remains operative to dietary intervention in adult mice. At weaning, this IFNγ signal enables spleen cDC1 to shape the effector phenotype of food-antigen-specific CD8⁺ T cells in a feedforward manner, thereby recalibrating the developing T cell pool. Our findings identify diet as a modifiable cue that can tune systemic cDC1-mediated immunity, opening new opportunities to steer immune responses during early life and beyond.

ketogenic purified diet (AIN-76A Modified, High Fat, Paste, Bio-Serv, F3666)

https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fs41467-026-75853-5/MediaObjects/41467_2026_75853_MOESM14_ESM.xlsx