Journal article
Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan
Carolien E van de Sandt, Thi HO 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, Alice Harper, Samuel J Redmond, Hayley A McQuilten, Tejas Menon, Sneha Sant, Xiaoxiao Jia, Kate Pedrina, Theo Karapanagiotidis Show all
Nature Immunology | Nature Research | Published : 2023
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 epitop..
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Grants
Awarded by We thank the participating donors involved in the study as well as B. McCudden and J. Mitchell for their medical support. We thank staff at the Melbourne Cytometry Platform for the technical support and assistance. This work was supported by the ARC-Discov
Awarded by ARC-Discovery grant
Awarded by Clifford Craig Foundation
Awarded by Research Grants Council of the Hong Kong Special Administrative Region, China
Awarded by European Union
Awarded by UoM Establishment Grant
Awarded by National Health and Medical Research Council, Australia
Awarded by NHMRC Emerging Leadership Level 1 Investigator Grant
Awarded by NHMRC Leadership Investigator grants
Awarded by NHMRC Senior Research Fellowship
Awarded by NHMRC Senior Principal Research Fellowship
Funding Acknowledgements
We thank the participating donors involved in the study as well as B. McCudden and J. Mitchell for their medical support. We thank staff at the Melbourne Cytometry Platform for the technical support and assistance. This work was supported by the ARC-Discovery grant to K.K., F.L. and S.G. (DP190102704), the Clifford Craig Foundation Project Grant to K.F. and K.K. (186), the Research Grants Council of the Hong Kong Special Administrative Region, China (T11-712/19-N) to K.K. and the NHMRC Leadership Investigator Grant to K.K. (1173871). C.E.S. received funding from the European Union's Horizon 2020 research program under the Marie Sklodowska-Curie Grant agreement (792532) and is supported by the ARC-DECRA Fellowship (DE200100185) and the UoM Establishment Grant. F.L. was supported by the National Health and Medical Research Council, Australia (project grant 1121643) and Career Development Fellow (1128416). T.H.O.N. is supported by the NHMRC Emerging Leadership Level 1 Investigator Grant (1194036), N.A.G. is supported by the ARC-DECRA Fellowship (DE210100705), E.B.C. is supported by a NHMRC Peter Doherty Fellowship (1091516), J.R. and N.L.L.G. are supported by NHMRC Leadership Investigator grants, S.G. is supported by NHMRC Senior Research Fellowship (1159272), D.I.G. was supported by an NHMRC Senior Principal Research Fellowship (1117766) and subsequently by an NHMRC investigator grant (2008913). J.C.C., A.A.M., M.V.P. and P.G.T. are supported by NIH NIAID R01 AI136514, U01AI150747 and ALSAC at St. Jude. We also thank L. Wooldridge (University of Bristol) for the provision of vectors encoding CD8 mutants of soluble HLA-A*02:01 molecules.