The neonatal liver orchestrates T cell tolerance through specialized microniches

Abstract: At birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we identify and characterize the neonatal liver as a central hub of systemic CD4? T cell tolerance induction. In week 1–2, the liver hosts a developmentally encoded, microbiota-independent expansion of Foxp3? regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4? T cell (Tconv). Mechanistically, CCR7? cDC1 form MHCII-dependent tolerogenic foci distributed across parenchyma, where Treg clusters expand in close apposition to dendritic cells. PD-L1 (/PD-L2) checkpoints within these foci selectively increase Tregs without unleashing Tconv. Importantly, this transient, neonatal Treg program causes an enhanced chronicity of early life hepatotropic virus infection, but also induces long term metabolic priming and protects the adult liver from MASLD development. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions and identifies neonatal T cells as potential players in the increased chronicity of chronic hepatitis virus infection in neonates. One-sentence significance cDC1-assembled, checkpoint-tuned microclusters in the neonatal liver expand Tregs independent of microbiota, control Tconv activation, and shape the infection outcome in the neonate and metabolic liver disease later in the adult host. Suggested keywords neonatal immunity; regulatory T cells; dendritic cells; liver tolerance; checkpoint signaling (?)