Multi‐Omics Analysis of Human Blood Cells Reveals Unique Features of Age‐Associated Type 2 CD8 Memory T Cells

Aging impacts immune function, but the mechanisms driving age‐related changes in immune cell subsets remain unclear. To explore age‐dependent changes in immune cell populations, we analyzed human peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20–82 years using a 36‐color spectral flow cytometry panel focused on T cells. We identified a unique population of memory CD8 T cells, which lack CXCR3 and produce a Th2‐like cytokine response, and accumulate with age. We discovered an age‐dependent bias in naïve CD8 T cells toward Th2 cytokine production, accompanied by transcriptional and epigenetic changes supporting this phenotype. Moreover, health outcome association analysis linked the accumulation of these unique CXCR3‐ central memory CD8 T cells to asthma, chronic liver conditions, and type 2 diabetes. Together, our results support the model that an age‐dependent drift in epigenetic regulation toward a Th2‐like phenotype drives a pathogenic Th2‐like immune population.