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

2023; Nature Portfolio; Volume: 24; Issue: 11 Linguagem: Inglês

10.1038/s41590-023-01633-8

1529-2916

Carolien E. van de Sandt, Thi H. O. Nguyen, Nicholas A. Gherardin, Jeremy Chase Crawford, Jerome Samir, Anastasia A. Minervina, Mikhail V. Pogorelyy, Simone Rizzetto, Christopher Szeto, Jasveen Kaur, Nicole Ranson, Sabrina Sonda, A. M. Harper, Samuel J. Redmond, Hayley A. McQuilten, Tejas Menon, Sneha Sant, Xiaoxiao Jia, Kate Pedrina, Theo Karapanagiotidis, Natalie Cain, Suellen Nicholson, Zhenjun Chen, Ratana Lim, E. Bridie Clemens, Auda A. Eltahla, Nicole L. La Gruta, Jane Crowe, Martha Lappas, Jamie Rossjohn, Dale I. Godfrey, Paul G. Thomas, Stéphanie Gras, Katie L. Flanagan, Fabio Luciani, Katherine Kedzierska,

Immunotherapy and Immune Responses

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-M1 58–66 (A2/M1 58 ) 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/M1 58 + 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.