Multimodal single-cell analysis uncovers transcription factor networks underlying T-cell aging

Shaigan, M.; Puri, D.; Fornero, G.; Kruger, R.; Steiger, M.; Klump, H. J.; Meissner, A.; Kretzmer, H.; Wagner, W.; Gesteira Costa Filho, I.

doi:10.64898/2026.05.19.726137

bioRxiv · 10.64898/2026.05.19.726137

Multimodal single-cell analysis uncovers transcription factor networks underlying T-cell aging

Shaigan, M.·Puri, D.·Fornero, G.·Kruger, R.·Steiger, M.·Klump, H. J.·Meissner, A.·Kretzmer, H.·Wagner, W.·Gesteira Costa Filho, I.

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Abstract

Aging of the immune system is associated with chronic inflammation and impaired immune function, yet the regulatory mechanisms underlying these changes remain incompletely understood. Here, we generated paired single-cell transcriptomic and chromatin accessibility profiles from peripheral blood mononuclear cells of young and old healthy donors to characterize immune aging at single-cell resolution. Using an integrative computational framework for multi-omic single-cell analysis, we detected pronounced age-associated changes in T cells, including loss of naive CD8+ T cells and expansion of differentiated memory and effector populations. Aging was accompanied by increased inflammatory signaling and reduced oxidative phosphorylation programs. Enhancer-based gene regulatory network analyses identified a reduced role of TCF7 and increased activity of inflammatory regulators, including FOSL2, in aged T cells. Integration with genetic association and eQTL datasets further supported the functional relevance of age-associated regulatory regions and their target genes.

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Shaigan, M., Puri, D., Fornero, G., Kruger, R., Steiger, M., Klump, H. J., Meissner, A., Kretzmer, H., Wagner, W., Gesteira Costa Filho, I.. 2026-05-21. Multimodal single-cell analysis uncovers transcription factor networks underlying T-cell aging. https://doi.org/10.64898/2026.05.19.726137

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