Specialised immune cells, capable of killing off infections and cancers, can escape their own destructive properties through the action of a protective outer shield, researchers from Peter Mac and the University College London have discovered.
This work helps to explain how our immune system can be so effective in killing rogue cells, and why some cancers may be more resistant to killing by the immune system.
Cytotoxic T lymphocytes (CTL) kill through the action of a protein, perforin, which punches holes into the outer membranes of target infected and cancerous cells, allowing a cargo of toxic molecules to enter the cells, causing it to die.
Exactly how killer CTLs avoid punching destructive holes in their own membranes has remained, until now, a mystery.
New research, published in Nature Communications, has revealed that the key to CTL self-protection lies in an ordered and electrically-charged envelope that wraps the immune cells in an impenetrable protective layer.
“All cells in our body are surrounded by a membrane made up of millions of tiny lipid molecules,” explain senior authors on the study, A/Prof Ilia Voskoboinik, Head of Killer Cell Biology Laboratory at Peter Mac, and Prof Bart Hoogenboom of Centre for Nanotechnology at University College London.
“We found that the lipids in the membranes of CTLs are more tightly packed together compared to the cells that they are trying to kill. The more densely packed the lipids, the more impenetrable the membrane is to the action of perforin.”
When the researchers artificially disrupted the order of lipids in the membranes of CTLs, they became more sensitive to perforin. They also found that some of the lipids in the CTL membrane were negatively charged, which helped to capture perforin molecules and prevent self-damage.
“We have long known that local lipid order can change how cells communicate with each other, but it was rather surprising that these precise physical membrane properties can also provide such an important layer of protection against molecular hole-punchers,” explains Adrian Hodel, joint lead author from the Hoogenboom laboratory at University College London, who screened and studied many membrane systems for this work.
These results confirm the importance of lipid organisation and charge in determining whether or not a cell is capable of being killed by CTLs. This could have important implications for new anti-cancer immunotherapies that activate the immune system to recognise and kill cancers.
“The efficacy of current immunotherapy approaches relies on the ability of CTLs to kill tumour cells through the activity of perforin,” explains Jesse Rudd-Schmidt, joint lead author on the study who conducted research within A/Prof Voskoboinik’s lab at Peter Mac.
“If some cancer cells can reorganise their outer membranes to resemble the tightly packed and negatively-charged membranes of CTLs, this could protect them from being killed by the immune system. This could in part explain some of the large variability in patient response to cancer immunotherapies.”
The paper is titled “Lipid order and charge protect killer T cells from accidental death”.
This work was kindly funded by the Australian National Health and Medical Research Council, by the Peter Mac Foundation, by the UK Biotechnology and Biological Sciences Research Council and Engineering and Physical Sciences Research Council, and by the Sackler Foundation.
For more information or to arrange an interview please contact the Peter Mac Communications team on 0417 123 048.