Eva-Lena Stange, Trong-Hieu Nguyen, Dustyn Mendoza, Aiara Lobo Gomes, Marlene Sophia Kohlhepp, Jonas Pes, Shahed Al Bounny, Julian Brueck, Yunus Cetiner, Urs Moerbe, Milas Ugur, Cristina Kalbermatter, Jarrett Lopez-Scarim, Aline Dupont, Susan A. V. Jennings, Julia Heckmann, Aaron Silva-Sanchez, Solveig Runge, Christoph Kuppe, Oliver Pabst, Thomas Clavel, Dorothee Viemann, Stephan P. Rosshart, Vuk Cerovic, Stephanie C. Ganal-Vonarburg, Adrien Guillot, Eva Billerbeck, Mathias W. Hornef, Natalia Torow
After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1–2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4⁺ T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions.
