White blood cells are protected from harm because of the properties of their cell envelopes, according to a joint Australian-UK study.
For the first time, scientists have ascertained how cytotoxic T-cells avoid being killed by their own actions. They say their findings could help them to understand why some tumours are more resistant than others to recently developed cancer immunotherapies.
The research, published in the journal Nature Communications, highlights the role of the physical properties of the white blood cell envelope.
Professor Bart Hoogenboom, from University College London, said cytotoxic lymphocytes rid the body of disease by punching holes in rogue cells and by injecting poisonous enzymes inside.
“Remarkably, they can do this many times in a row, without harming themselves,” he said. “We now know what effectively prevents these white blood cells from committing suicide every time they kill one of their targets.”
The team made the discovery by studying the protein perforin. They found that its attachment to the cell surface strongly depends on the order and packing of the lipids in the membrane that surrounds and protects the white blood cells.
They found that more order and tighter packing of the lipid molecules led to less perforin binding. When they artificially disrupted the order of the lipid in the white blood cells, the cells became more sensitive to perforin.
However, they also found that when the white blood cells were exposed to so much perforin that some of it stuck to their surface, the bound perforin still failed to kill the white blood cells.
This indicated that there is another layer of protection. The researchers found that this was the negative charge of some lipid molecules, phosphatidylserine, which is sent to the cell surface. This bound the remaining perforin and blocked it from damaging the cell.
Joint first author Dr Adrian Hodel said: “We have long known that local lipid order can change how cells communicate which each other, but it was rather surprising that the precise physical membrane properties can also provide such an important layer of protection against molecular hole-punchers.”
Jesse Rudd-Schmidt, joint first author from the Peter MacCallum Cancer Centre in Melbourne, added: “What we have found helps to explain how our immune system can be so effective in killing rogue cells. We are now also keen to investigate if cancer cells may use similar protection to avoid being killed by immune cells, which would then explain some of the large variability in patient response to cancer immunotherapies.”
Rudd-Schmidt JA, Hodel AW, Noori T, Lopez JA, Cho HJ, Verschoor S, Ciccone A, Trapani JA, Hoogenboom BW, Voskoboinik I (2019) “Lipid order and charge protect killer T cells from accidental death”, Nature Communications, doi: 10.1038/s41467-019-13385-x