Alexandru, A. C. | bioRxiv Science

bioRxiv2025

Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 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, accumulate with age. We discovered an age-dependent bias in naive 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 towards a Th2-like phenotype drives a pathogenic Th2-like immune population.

immunology↗

bioRxiv2025

Accumulation of SA-βGal High Cells in Human Naive T Cell Compartments Reveals a Stress-Adapted, Senescent-Like State

Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated {beta}-galactosidase (SA-{beta}Gal) activity is a well-established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naive CD4 and CD8 T cells displaying high SA-{beta}Gal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-{beta}Gal-high naive T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naive CD4 SA-{beta}Gal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naive T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.

immunology↗