Multi-omics Analysis Revealed Unique Features of Age-associated Type2 CD8 Memory T cells

Aging impacts immune function, yet how and why various subsets of immune cells change during aging is still incompletely understood. Here, we analyzed peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20–82 years to uncover previously unrecognized age-dependent changes, using a 36-color spectral flow cytometry panel focused on T cells. We found that CXCR3- memory CD8 T cells, which produce a Th2-like cytokine response, accumulate with age. Comprehensive multi-omics analysis revealed transcriptional and epigenetic signatures that support Th2-like function. Importantly, we also identified an age-dependent bias towards the production of Th2 cytokines after activation in naive CD8 T cells, along with transcriptional and epigenetic changes supporting this outcome. Moreover, health outcome association analysis demonstrated a pathogenic feature of CXCR3- CM accumulation. Together, our results suggest that age-dependent corruption of epigenetic programming may cause the aberrant emergence of this potentially pathogenic Th2-like immune population Overall design: RNA-seq profiling of FACS sorted 5 subsets of human CD8 T cells (Naïve, CXCR3- CM, CXCR3+ CM, CD28+CD57+ EM and CD57+ EMRA).