Single-cell map of the healthy human immune system across the lifespan reveals unique infant immune signatures

The human immune system undergoes dynamic remodeling from infancy through old age. We profiled PBMCs from 167 healthy individuals (ages 2 months to 105 years): infants (n=36), children (n=26), adolescents (n=20), young adults (n=24), middle‑aged (n=16), older adults (n=33) and oldest old (n=12) using scRNA‑seq and snATAC‑seq (n=23). MAIT and γδ T cells showed a “rise and fall” pattern, rising in childhood, peaking in young adulthood, and declining with age. Conventional CD8⁺ T cells were most profoundly altered with age, with decreasing naïve and increasing GZMK⁺ and TEMRA cells. The oldest old had increased TEMRA, adaptive NK, and KLRF1⁺ γδ T cells. Infants showed increased CD16⁺ monocytes and pDCs, constitutive interferon‑stimulated gene expression, and expanded SOX4⁺ naïve T cells. Inflammatory and stress‑response pathways increased with age, while interferon pathways declined. This map provides insights into human immune system dynamics across the lifespan, emphasizing unique features of the infant immune system.