The cells giving our immune system more punch

Infection-fighting T cells tied to specific organs have emerged as potent killers and scientists are racing to understand how to harness them to fight diseases including cancer

Andrew Trounson, University of Melbourne

Published 5 August 2018

There is a mysterious life-and-death battle going on every day inside us.

Our immune system works relentlessly to maintain a precarious balance between killing infections and killing us. And much of what’s going on remains a black box.

Each year, the text books are updated as researchers discover that what they thought was happening, actually isn’t quite right at all.

A dendritic cell (centre) presenting an antigen to T cells (bright blue) and effects an immune response. Picture: Getty Images

“The more we know the more we realise how much we don’t know” says Dr Laura Mackay, from the Peter Doherty Institute for Infection and Immunity and the University of Melbourne. As a specialist on our immune system, she says working in this field is like working on an “endless puzzle.”

But there is a piece in the puzzle she and others are investigating that is now starting to fall into place.

And it brings with it the potential of a new way to make effective vaccines for a variety of diseases, from malaria and influenza, to the different types of cancer.

This jigsaw piece is a type of T cell called ‘tissue-resident memory T cells’, or Trm cells’. T cells are infection-fighting white blood cells which, like B cells, once exposed to an infection adapt to it, or “remember” it.

That means they are able to kill an infection more effectively when they encounter it again.

But unlike normal T cells that circulate in our blood streams, Trm cells live in a specific organ like the liver or the skin. What has been discovered in recent years is that these Trm cells are particularly potent killers of localised infections.

Until recently, research on developing T cell-based vaccines have focused on T cells that circulate in the blood. But Dr Mackay says that for certain diseases, research on blood T cells hasn’t yielded the breakthrough treatments that were hoped for.

Dr Laura Mackay and colleagues working to isolate resident T cells from tissue. Picture: Supplied

“What is becoming more and more apparent, is that we’d been looking in the wrong place, and that we need to also be focusing our research on these Trm cells in the tissue, not just T cells in the blood,” says Dr Mackay.

In June, Dr Mackay’s ongoing research into Trm cells was awarded the US-based Michelson Medical Research Foundation’s Prize for Human Immunology and Vaccine Research, and last year she received a Howard Hughes Medical Institute (HHMI) award and Bill & Melinda Gates International Research Scholarship.

It had long been assumed that T cells found in the tissues would behave in a similar way to those in the blood, and it is only in the last ten years or so that we have discovered just how different they are. Part of the delay is that isolating resident T cells from tissue is a lot harder than isolating T cells from blood.

“You are looking at six to eight hours of lab work compared with perhaps just the hour it takes to extract T cells from the blood system.”

It was pioneering work in 2009 by separate teams, one led by the late Professor Leo Lefrancois and David Masopust from the University of Connecticut and the other by Dr Mackay’s own mentor Professor Frank Carbone at the University of Melbourne, that was instrumental in refocusing research onto Trm cells.

“Boosting T cells in the blood doesn’t help much to stop an infection that originates in the tissue. You want Trm cells that can be engineered at the site of infection so they can stop the infection before it spreads around the body,” says Dr Mackay.

Trm cells are specialised to the organ where an infection may start, like the mucus membrane in the mouth, or in the case of malaria, the liver.

“This specialisation makes Trm cells more effective.”

And emerging evidence is backing this up.

Patient with vitiligo, where patches of the skin lose pigmentation, which are more resistant to skin cancer. Picture: Jame Heilman/Wikipedia

It had long been noted that patients with vitiligo, a condition in which parts of the skin lose pigmentation, had a lower risk of developing skin cancer, but we didn’t know why.

Researchers have since found that people with vitiligo have higher numbers of Trm cells in the affected skin site and that these Trm cells are also protective against skin cancer.

Similarly, a research collaboration between the Peter MacCallum Cancer Centre, the Peter Doherty Institute and the University of Melbourne has found that higher numbers of Trm cells in a woman’s breast is associated with improved breast cancer survival rates.

“It now looks like the more Trm cells you have the better protected you are against cancer,” says Dr Mackay. “The challenge then is to understand how we can boost Trm cell generation to make better immune therapies.”

Dr Mackay’s own laboratory is investigating the genetics of Trm cells to understand how they could be switched on to attack specific infections or cancer by manipulating genes and other molecules. She is also looking at how blood T cells can be turned into Trm cells when you need them.

“During an immune response, the numbers of T cells that become Trm cells is quite small, so we want to flip that and produce more Trm cells. Everything we do is aimed at boosting Trm cells because these are the cells clearing cancers and infections.”

One of the challenges in boosting Trm cells is to maximise the disease-fighting cells without causing damaging inflammation that can be associated with immune responses.

Whether a Trm is protective or damaging is determined by the triggering of specific genes and Dr Mackay is using genetic engineering to try to boost the protective traits of Trm cells while minimising the pathological ones.

Dr Laura Mackay and colleagues examining Trm cells in the laboratory. Picture: Supplied

“We need to understand how we can strike the right balance between the protective and pathological traits of Trm cellswhile still preserving their overall effectiveness,” says Dr Mackay.

So, are we getting close to unlocking the mystery of our immune system?

Dr Mackay isn’t so sure it will ever by wholly unlocked, but she says each step brings with it the potential for new life-saving therapies.

“For me it is a never-ending story, and I want to know what happens next.”

Banner Image: Electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red)/NIH on Flickr

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