Neonatal regulatory T cells persist into adulthood across multiple tissues with high enrichment in the skin.

Foxp3+ regulatory T cells (Tregs) reside in both lymphoid and nonlymphoid organs, where they play a crucial role in immune tolerance and tissue homeostasis. In mice, Tregs begin colonizing these tissues shortly after birth, contributing to long-term immune response regulation therein. However, the kinetics of Treg generation across different tissues remains unclear. Here, we investigate Treg ontogeny from birth to adulthood in various tissues. In lymphoid organs, the adult Treg pool is continuously replenished with cells generated at different ages. In contrast, the skin retains a large fraction of Tregs that colonize the tissue during the neonatal period, with minimal turnover in adulthood. The liver, lungs, and colon exhibit intermediate Treg renewal dynamics. Notably, neonatal Tregs that persist into adulthood display a more activated phenotype and express markers associated with tissue-resident Tregs and type 2 immunity. Our findings reveal tissue-specific differences in Treg generation kinetics and highlight a major phenotypic shift between neonatal and adult-derived Tregs.