Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 CD8 Memory T cells

Hiroyuki Matsui; Marlene Cervantes; Mir Mubashir Khalid; Alan Tomusiak; Varun Bhamidipati Dwaraka; Jorge Landgrave-Gómez; Prasanna Vadhana Ashok Kumaar; Qingwen Jia Xiaohan Chen; Jessica Ann Lasky-Su; Jake Stone; Ritesh Tiwari; Ryan Kwok; Shuntaro Ichikawa; Benjamin D Ambrose; Rebeccah R. Riley; Genesis Vega Hormazabal; Ariel Floro; Andreea Cristina Alexandru; Ryan C. Smith; Birgit Schilling; Herbert G. Kasler; Eric Verdin

doi:10.1111/acel.70393

ImmunologyAging CellFeb 1, 2026

Peer-reviewed journal article

Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 CD8 Memory T cells

Hiroyuki Matsui, Marlene Cervantes, Mir Mubashir Khalid iD, Alan Tomusiak iD, Varun Bhamidipati Dwaraka iD, Jorge Landgrave-Gómez iD, Prasanna Vadhana Ashok Kumaar iD, Qingwen Jia Xiaohan Chen iD, Jessica Ann Lasky-Su iD, Jake Stone, Ritesh Tiwari, Ryan Kwok iD, Shuntaro Ichikawa, Benjamin D Ambrose, Rebeccah R. Riley iD, Genesis Vega Hormazabal, Ariel Floro iD, Andreea Cristina Alexandru iD, Ryan C. Smith iD, Birgit Schilling iD, Herbert G. Kasler iD, Eric Verdin iD

Abstract

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.

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