Doğuş Altunöz, Ramin Shakiba, Kaushikk Ravi Rengarajan, Hamsa Narasimhan, Nikos E. Papaioannou, Sadiq Nasrah, Jessica Vetters, Maria L. Richter, Maria Parra Reyes, Nadine Nuschele, Denise Messerer, Sabine Schwamberger, Andreas Goschin, Dimitrios Starfas, Melanie Schmid, Tobias Straub, Michele Proietti, Katrin Böttcher, Maria Colomé-Tatché, Dirk Haller, Jan P. Böttcher, Stephanie Ganal-Vonarburg, Sophie Janssens, Christian Schulz, Anne B. Krug, Barbara U. Schraml
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.
