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

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