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24 Apr 2021

Distinguishing between foreign invaders and healthy tissues

A key element of most anti-viral immune responses is the ability of the immune system to distinguish between a foreign invader and healthy tissues – referred to as ‘self’.  This is to allow for destruction of virus-infected cells by ‘killer’ T cells without killing healthy cells. 

What happens however, when parts of the virus targeted by the immune system are almost identical to features of ‘self’? How does the immune system target virus-infected cells without causing too much collateral damage?

Researchers at the Doherty Institute have uncovered a new way that the immune system strikes this delicate balance.

Led by University of Melbourne Professor Andrew Brooks, Co-Deputy Director of the Doherty Institute and Dr Lucy Sullivan, a Senior Research Fellow at the Doherty Institute, the research published today in Science Immunology focuses on how receptors normally found on another type of cell called “natural killer” cells fine-tune the response of these killer T cells. This allows for killer T cells to target cells infected with human cytomegalovirus (CMV), a virus that causes major problems for people who are immunosuppressed such as transplant recipients, whilst sparing healthy tissues.

“We have been trying to understand how T cells, specific to fighting a virus, can see those virally-infected cells, when the part of the virus they recognise is nearly identical to self-molecules,” Dr Sullivan said.

“In an ideal world, the T cells have to be able to make that distinction because you don’t want a situation where your T cells that are trained to kill virus-infected cells, start attacking your own healthy cells just because they express something that resembles the virus.

“While T cells use a receptor called the T cell receptor to recognise virus infected cells, we found that these CMV-specific T cells make use of an additional set of receptors to either boost recognition of virus-infected cells, or alternatively to act as a brake to prevent them attacking healthy cells that have molecules that that are nearly identical those in CMV. These other receptors dampen the T cell response so as not to overreact.”

“So what we found is that  it is the balance of signals, some of which are activating, some of which are inhibitory that enables the killer T cells to navigate  the fine line of destroying virus-infected cells without unduly damaging healthy cells.”

Professor Brooks adds that these findings have broader implications for T cell biology.

“Further work will look at how we can harness these receptors to enhance T cell responses Currently, a number of ground breaking immunotherapies used to combat cancer are based on releasing  ‘brakes’ on  killer T cells, enabling them to kill cancer cells. In this case, we have found examples of new some brakes which we might target as well as a potential accelerator which might be used to enhance the killer T cell response” Professor Brooks said.

This research was done in collaboration with local groups, including the Kedzierska lab from the Doherty Institute and researchers from The Kirby Institute, UNSW, as well as international collaborators from the University of Genoa, Italy and University of Oslo, Norway.

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