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Remodeling of the Immune System across Human Lifespan at Single Cell Resolution

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.

This study includes 95 samples generated in-house (this submission) and 72 samples obtained from four publicly available datasets, for a total of 167 samples.

Participants were grouped into seven age categories:

• Infants (2 months–2 years): n = 36

• Children (2–12 years): n = 26

• Adolescents (12–18 years): n = 20

• Young adults (18–40 years): n = 24

• Middle-aged adults (45–65 years): n = 16

• Older adults (65–85 years): n = 33

• Oldest old (85–105 years): n = 12

The public datasets are described below:

• Deng et al. (GSE231906): n = 21

• Wang et al. (syn61609846): n = 45

• Wang et al. (GSE168732): n = 3

• Zhong et al. (GSE206295): n = 3

For epigenetic analyses, single nucleus ATAC sequencing (snATAC seq) data from 23 healthy PBMC donors were utilized, distributed across age groups as follows:

• Infants and children: n = 9

• Adolescents: n = 3

• Young and middle aged adults: n = 6

• Older adults: n = 5

The raw data (fastq files) from participants HY13, HY18 and HY19 will not be included in the dataset per consent. HI17 and HI23 samples originate from the same infant collected at two time points (2 months for HI17 and 11 months for HI23).