Severe viral infections and malignancies are known to weaken the immune system, particularly T cells, a state known as immunological “exhaustion.” Overcoming immunological exhaustion is a key goal in the development of innovative drugs for cancer or severe viral infections.
According to a study that was published in the journal “Immunity,” researchers from Melbourne have developed a method to improve the immune response in the face of severe viral infections. Immune weariness may be prevented by understanding why it happens and how to do so, according to a team from the Peter Doherty Institute of Infection and Immunity (Doherty Institute) led by Dr. Sarah Gabriel, Dr. Daniel Utzschneider, and Professor Axel Kallies of the University of Melbourne.
The group had already discovered that while some T cells lost their function and ran out of energy in a matter of days, others, known as Tpex cells, were able to keep functioning for a considerable amount of time.
“This idea that you need to overcome exhaustion and make T cells better is at the heart of immunotherapy,” Professor Kallies said.
“While immunotherapy works really well, it is only effective in around 30 per cent of people. By discovering a way to prime T cells differently so they can work efficiently in the long run, we may be able to make immunotherapy more effective in more people,” he added.
The researchers has now discovered a mechanism explaining how Tpex cells can retain their fitness over extended periods of time, as reported in their most recent work, which was published today in Immunity. According to Professor Kallies, the discovery may increase the likelihood that immunotherapy may be effective.
In contrast to cells that were running out of energy, Tpex cells have lower activity of the nutritional sensor mTOR, which controls cellular energy generation and expenditure, according to Dr. Gabriel.
This means that Tpex cells were able to slow down their activity so they could continue to operate for a longer period of time. It’s the equivalent of running a marathon at a slower pace rather than a sprint at full speed.
Dr. Utzschneider emphasised that turning on the immune system requires striking a balance.
You don’t want to be left walking the race, Dr. Utzschneider said. “You don’t want to attenuate the reaction too much to the point where the response becomes useless.”
The following step was to identify the mechanism that was causing this. We found that early in an infection, Tpex cells were exposed to higher levels of the immunosuppressive molecule TGF?? By lowering the activity of mTOR and so suppressing the immunological response, this molecule effectively serves as a brake.
It’s exciting to note that the scientists were able to exploit this finding to enhance the immune response to severe viral infection.
Dr. Gabriel explained that early mTOR inhibitor treatment of mice improved the immune response to the illness.
Additionally, mice who had been given the mTOR inhibitor responded better to checkpoint inhibition, a treatment that is frequently given to humans with cancer.