Collaborative research between the Universities of Dundee and Cambridge has uncovered how ‘assassin’ immune cells are able keep on killing as they hunt down cancer cells, repeatedly reloading their toxic weapons.
Cytotoxic T cells, an important component of our immune system, are specialist white blood cells that are trained by our immune system to recognise and eliminate threats – including tumour cells and cells infected with invading viruses.
Researchers at the University of Dundee have been working with the University of Cambridge to help further understand the exact mechanisms that influence T-cell function using Dundee’s state-of-the-art fingerprints proteomics facility.
Professor Gillian Griffiths from the Cambridge Institute for Medical Research, who led the research, explained, “T cells are trained assassins that are sent on their deadly missions by the immune system. Once a T cell has found its target, it binds to it and releases its toxic cargo. But what is particularly remarkable is that they are then able to go on to kill and kill again.”
To date, the mechanism of how T cells control the refuelling of their toxic weapons so that they can keep on killing has not been well understood. Understanding the details of this basic process could ultimately help in the long-term scientific goal of designing and engineering more efficient T cells to fight cancer. This study, now published in Science, has made a significant breakthrough as it shows that the refuelling of the T cells’ toxic weapons is regulated by mitochondria. Mitochondria are often referred to as a cell’s batteries as they provide the energy that power their function. However, in this case the mitochondria use a different mechanism to ensure the killer T cells have sufficient ‘ammunition’ to destroy their targets.
The team in Cambridge discovered that T cells with problems in mitochondria were defective killers that were unable to replenish key proteins required for killing. However, they needed to know the extent of the defect. Using the cutting-edge mass spectrometry-based proteomics, the University of Dundee’s School of Life Sciences Fingerprints Proteomics Facility were able to provide the answer. Dundee researchers discovered that it was specifically the proteins that make up the toxic ammunition that were unable to be quickly manufactured and reloaded when the mitochondria was compromised.
Dr Julia Marchingo from the School of Life Sciences explained, “The state-of-the-art proteomics technology available here in the University of Dundee enabled accurate mapping of the proteins that changed when T cells have defective mitochondria.”
Professor Doreen Cantrell, laboratory leader of the Dundee collaborative work added “Having this top-of-the-line technological capability here in Dundee means that scientists in academia and industry from all over the UK come to us for our expertise. This creates really exciting collaborative opportunities to make important discoveries in both basic science and clinical research.”
The research was funded by the Wellcome Trust.
Reference: Lisci, M et al. Mitochondrial translation is required for sustained killing by cytotoxic T cells. Science; 14 Oct 2021; DOI: 10.1126/science.abe9977