Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan

van de Sandt, Carolien E., Nguyen, Thi H. O., Gherardin, Nicholas A., Crawford, Jeremy Chase, Samir, Jerome, Minervina, Anastasia A., Pogorelyy, Mikhail V., Rizzetto, Simone, Szeto, Christopher, Kaur, Jasveen, Ranson, Nicole, Sonda, Sabrina, Harper, Alice, Redmond, Samuel J., McQuilten, Hayley A., Menon, Tejas, Sant, Sneha, Jia, Xiaoxiao, Pedrina, Kate, Karapanagiotidis, Theo, Cain, Natalie, Nicholson, Suellen, Chen, Zhenjun, Lim, Ratana, Clemens, E. Bridie, Eltahla, Auda, La Gruta, Nicole L., Crowe, Jane, Lappas, Martha, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Godfrey, Dale I., Thomas, Paul G., Gras, Stephanie, Flanagan, Katie L., Luciani, Fabio and Kedzierska, Katherine 2023. Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan. Nature Immunology 24 , 1890–1907. 10.1038/s41590-023-01633-8

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Abstract

CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158–66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Research
ISSN:	1529-2908
Date of First Compliant Deposit:	26 October 2023
Date of Acceptance:	24 August 2023
Last Modified:	27 Oct 2023 13:15
URI:	https://orca.cardiff.ac.uk/id/eprint/163520

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