Important flu-fighting immune cells go M.I.A.

One of the body’s most important disease fighters retires and scientists don’t know why.

Killer T cells (also known as CD8+ T cells) are specialised lymphocytes that seek and destroy other cells that are infected with a virus or become cancerous.  

Once a problem cell is sighted, the killer binds to specific receptors on the target and destroys it.

But the effectiveness of this immune process appears to shift as we age, with changes in killer T cell efficiency now described in a multi-institutional study led by researchers from the Doherty Institute and UNSW published in Nature Immunology.

Their analysis investigated how killer T cells from newborns, school children, adults and people over 60 years recognise and respond to influenza viruses.

While children and adults have efficient immune responses, the process is less efficient once people turn about 60 years old.

The scientists have uncovered a surprising “clonal reset” of such cells in some people aged over 60. These primed killer T cells seemingly disappear, leaving remaining, less specialised T cells available to do the job.

“The specific T cell receptor – basically the molecule that allows the T cell to bind to the antigen – is actually most similar to the one from young, young children,” says Associate Professor Fabio Luciani from the School of Medical Sciences at UNSW Sydney, one of the senior researchers on the study.

“Those T cells that we found in aged population, they do recognise the viruses, and they have specific receptors that allowed them to recognize the pathogen… they are functional.

“The problem is that they don’t work as well as we observed in the younger [school-aged child and adult] population.”

The Doherty Institute’s Dr Carolien van de Sandt led the study investigating this peculiarity.

“We don’t know where they’ve gone, we just don’t detect them anymore,” she says.

To understand her research, one needs to dive into the nature of these T cells.

“You have a whole bunch of different [T] cells with slightly different receptors on the surface,” van de Sandt says.

“So when you first ‘see’ that infection, the best one gets selected.”

This is our prize fighter – tailor-made to take on influenza-infected opponents.

“They multiply, so the second time you see that [pathogen], these will respond really quicky.”

The other T cells in your body, the ones that weren’t selected to take on the threat, basically sit on the bench waiting for a call-up. That’s decades of waiting in reserve. In older people who lose their first-choice fighters, that leaves these suboptimal ones as the body’s next resort for battle.

“The second best gets selected, then the third best… and that’s what’s been happening here,” van de Sandt says.

“So, they’ve been sitting there waiting, and then once all the good ones are gone, they’re like ‘Okay, now it’s my turn’… but they’re not even close to what the best one is. Probably they’ve been around since childhood, but they’ve never been recruited.”

The end of the story is the beginning

Van de Sandt is less interested in solving the disappearance of certain cells in certain people, as she is in applying her findings to solving immunity issues.

The discovery suggests new possibilities for developing next-generation therapies that could prime or replenish the body’s immune response throughout the aging process.

“If you think of boosting these optimal cells at a younger age, and we can find a way to maintain them so they don’t disappear, we can maybe maintain [immunity] until very old age so that you’re protected for longer,” she says.

To identify optimal cells for future vaccines, the research team relied on the use of machine learning and single-cell genomics to analyse individual T cells at the molecular and proteomic – or protein – level.

With such granular analysis, they’ve built a substantial data profile of the nature of killer T cells within the body, which could be valuable in identifying candidates for recharging human immunity through new vaccines.

“We are using a lot of technology, which basically allows us to measure the molecular and proteomic makeup of individual T cells, but in each single cell we will measure the genes and the proteins that they express,” says Luciani. 

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