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.
| Original language | English |
|---|---|
| Pages (from-to) | 1890-1907 |
| Number of pages | 18 |
| Journal | Nature immunology |
| Volume | 24 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2023 |
Keywords
- Aged
- CD8-Positive T-Lymphocytes
- Epitopes, T-Lymphocyte/genetics
- Humans
- Infant, Newborn
- Longevity
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell/genetics
- T-Lymphocytes, Cytotoxic
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In: Nature immunology, Vol. 24, No. 11, 11.2023, p. 1890-1907.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan
AU - van de Sandt, Carolien E
AU - Nguyen, Thi H O
AU - Gherardin, Nicholas A
AU - Crawford, Jeremy Chase
AU - Samir, Jerome
AU - Minervina, Anastasia A
AU - Pogorelyy, Mikhail V
AU - Rizzetto, Simone
AU - Szeto, Christopher
AU - Kaur, Jasveen
AU - Ranson, Nicole
AU - Sonda, Sabrina
AU - Harper, Alice
AU - Redmond, Samuel J
AU - McQuilten, Hayley A
AU - Menon, Tejas
AU - Sant, Sneha
AU - Jia, Xiaoxiao
AU - Pedrina, Kate
AU - Karapanagiotidis, Theo
AU - Cain, Natalie
AU - Nicholson, Suellen
AU - Chen, Zhenjun
AU - Lim, Ratana
AU - Clemens, E Bridie
AU - Eltahla, Auda
AU - La Gruta, Nicole L
AU - Crowe, Jane
AU - Lappas, Martha
AU - Rossjohn, Jamie
AU - Godfrey, Dale I
AU - Thomas, Paul G
AU - Gras, Stephanie
AU - Flanagan, Katie L
AU - Luciani, Fabio
AU - Kedzierska, Katherine
N1 - Funding Information: 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 Skłodowska-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. Funding Information: 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 Skłodowska-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. Publisher Copyright: © 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - Aged
KW - CD8-Positive T-Lymphocytes
KW - Epitopes, T-Lymphocyte/genetics
KW - Humans
KW - Infant, Newborn
KW - Longevity
KW - Receptors, Antigen, T-Cell, alpha-beta/genetics
KW - Receptors, Antigen, T-Cell/genetics
KW - T-Lymphocytes, Cytotoxic
UR - http://www.scopus.com/inward/record.url?scp=85172232426&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41590-023-01633-8
DO - https://doi.org/10.1038/s41590-023-01633-8
M3 - Article
C2 - 37749325
SN - 1529-2908
VL - 24
SP - 1890
EP - 1907
JO - Nature immunology
JF - Nature immunology
IS - 11
ER -