Biological sex impacts immune cell proportions and epigenetic profiles in the developing pediatric immune system

Age- and sex-related differences in immune cell compositions and immune outcomes have been identified in adult and aging populations, but a comprehensive and nuanced characterization of these changes during the rapid developmental window of early life is lacking. We explored the association with sex and age within the immune system in CHILD, a Canadian longitudinal pediatric cohort, leveraging DNA methylation (DNAm) from whole blood samples collected at ages one and five years (n=760 paired, 356 female and 404 male). Using DNAm-based computational cell type deconvolution, we observed changes in all twelve estimated immune cell type proportions between these ages in a pediatric population and found significant differences in the context of biological sex. We also identified distinct age- and sex-specific DNAm signatures in the immune system in the first five years of life. Notably, there were few age-specific DNAm changes and the sex-specific DNAm were consistent across this early life developmental window. We were then able to validate many of the sex-specific DNAm changes in separate pediatric cohorts. This insight not only enhances our understanding of pediatric immune maturation and system composition in a healthy population but highlights the existence of sex-based differences prior to puberty.