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‘Killer T-cell’ discovery could help combat flu – Australian study

A world-first discovery from Australian researchers unlocks the potential for the development of better vaccines and therapies against influenza viruses tailored to different age groups.

According to the team, led by the Doherty Institute and University of New South Wales Sydney, the study revealed special immune cells called “killer T cells” in older adults closely resemble those found in newborns and children, reports The Guardian.

Killer T cells play a critical role in the immune system by eliminating virus-infected cells and establishing long-term immunological memory.

The research examined these cells in four different age groups: newborns, school-aged children, adults and adults over 60.

Lead author Dr Carolien van de Sandt, a senior research fellow at the Doherty Institute, said it was previously believed that people maintain the same killer T cells throughout their life but that these cells became less effective as they became exhausted, or “fell asleep” as people become older.

However, the researchers discovered that the effective cells found in children and adults actually disappear in the elderly, to be replaced by new cells that are less able to recognise virus-infected cells.

And these new cells displayed gene profiles closely similar to T cells found in newborns, which still need to learn how to recognise influenza viruses, Van de Sandt said.

“They have the capacity to respond really well,” she said. “They look very similar on the inside – like young cells – but the outside is different and doesn’t recognise (virus-infected cells) anymore. It’s almost as if they need reading glasses.”

Van de Sandt compares the new, less effective cells to having a sword swopped with a kitchen knife: “You can learn how to use it, but it will never be as effective.”

Professor Katherine Kedzierska of the University of Melbourne, head of the human T cell laboratory at the Doherty Institute and a senior author on the paper – published in Nature Immunology – said the research would help understand how immunity changed over an individual’s lifespan, and has the potential to significantly advance the science of vaccination.

“This study is a turning point for research into ageing immunity. It has far-reaching implications and opens up new possibilities for the development of better vaccines and therapies tailored to different age groups,” she said.

The work was conducted in collaboration with Professor Fabio Luciani, co-senior author from UNSW Sydney, who said new machine learning methods were used to reconstruct how the influenza virus-specific killer T-cells develop over the lifespan.

“As individuals grow, killer T cells get stronger and more effective at eliminating infected cells, but they disappear in older adults, where they are taken over by cells with a lower killing capacity,” he said.

Prof James Trauer, head of epidemiological modelling at Monash University, who was not involved in the research, said “immunity to many pathogens – including influenza and Covid – is clearly strongly influenced by factors other than what we can measure through standard blood tests (ie serology)”.

“So understanding cellular immunological processes through studies like these is very important,” he said.

Study details

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

Carolien van de Sandt, Thi Nguyen, Katherine Kedzierska, et al.

Published in Nature Immunology on 25 September 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 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.

 

Nature Immunology article – Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan (Open access)

 

The Guardian article – Australian discovery of change in ‘killer T cells’ could help fight against influenza (Open access)

 

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