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bioRxiv · 10.64898/2025.12.23.696247

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

Matsui, H.·Cervantes, M.·Khalid, M. M.·Tomusiak, A.·Dwaraka, V.·Landgrave-Gomez, J.·Ashok Kumaar, P. V.·Chen, Q.·Lasky- Su, J.·Stone, J.·Tiwari, R.·Kwok, R.·Ichikawa, S.·Ambrose, B.·Riley, R. R.·Vega Hormazabal, G.·Floro, A.·Alexandru, A. C.·Smith, R.·Schilling, B. C.·Kasler, H. G.·Verdin, E.
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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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Matsui, H., Cervantes, M., Khalid, M. M., Tomusiak, A., Dwaraka, V., Landgrave-Gomez, J., Ashok Kumaar, P. V., Chen, Q., Lasky- Su, J., Stone, J., Tiwari, R., Kwok, R., Ichikawa, S., Ambrose, B., Riley, R. R., Vega Hormazabal, G., Floro, A., Alexandru, A. C., Smith, R., Schilling, B. C., Kasler, H. G., Verdin, E.. 2025-12-26. Multi-omics Analysis of Human Blood Cells Reveals Unique Features of Age-associated Type2 CD8 Memory T cells. https://doi.org/10.64898/2025.12.23.696247

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