Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan

Menon, Tejas, McQuilten, Hayley A., Samir, Jerome, Nguyen, Thi H. O., Lim, Ratana, Kaur, Jasveen, Rizzetto, Simone, Eltahla, Auda, Thomas, Paul G., Lappas, Martha, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Gras, Stephanie, Crowe, Jane, Flanagan, Katie L., Luciani, Fabio, Doherty, Peter C., van de Sandt, Carolien E. and Kedzierska, Katherine 2025. Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan. Proceedings of the National Academy of Sciences 122 (30) , e2501167122. 10.1073/pnas.2501167122

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Abstract

Central memory CD8+ T cells (Tcm) represent the prominent memory T cell subset in human blood, yet the persistence of T cell receptor (TCR) clonotypic and transcriptional features of epitope-specific Tcm pools across the human lifespan remains unknown. We analyzed Tcm CD8+ T cells specific for HLA-A*02:01-M158–66 (A2/M158; a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific Tcm CD8+ pools dominate influenza-specific memory A2/M158+CD8+ T cell responses from the early childhood until old age. Tcm gene signatures were largely maintained across the age groups, although self-renewal genes defined Tcm pools in children, while older adult Tcm A2/M158+CD8+ T cells displayed detoxication and stress profiles. TCRαβ diversity within Tcm A2/M158+CD8+ T cell pools was greater in children and older adults, when compared to adults. The key public-associated TCRαβ clonotypes largely persisted across the human lifespan, although their highest frequency was detected in adults, reflecting lower TCRαβ diversity in this group. Older adults displayed increased TCRαβ heterogeneity, underpinned by large TCRαβ clonotype expansions of private TCRαβ clonotypes. Our study highlights the importance of largely preserved virus-specific Tcm pools across the human lifespan and advocates for boosting persistent TCRαβ clonotypes within this key peripheral blood subset.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	28 July 2025
Date of Acceptance:	17 June 2025
Last Modified:	28 Jul 2025 16:00
URI:	https://orca.cardiff.ac.uk/id/eprint/180085

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