Researchers at the University of New South Wales, Australia, have discovered that one of our immune cells uses mechanical force to kill cancerous cells more efficiently. The cells are none other than T-cells or T-lymphocytes, a type of white blood cell that makes our body’s first line of defence. T-cells are specialised in killing foreign cells such as disease-causing pathogens, cancer cells, infected cells, etc. They are armed with lytic granules that release special proteins, perforin and granzymes for immune attack. Perforin kills cancer cells by creating holes in their cell membranes allowing granzyme to invade the cells and complete the action.
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How do T-cells work?
T-cells combine with targeted disease cells and form a bridge between the two called the ‘cytotoxic immunological synapse.’ Interestingly, researchers discovered that mechanical forces generated by and within the T-cells influence how effectively perforin can puncture cancer cell membranes. These physical forces push lytic granules towards the bridge or immunological synapse, where the killer proteins are released. Also, these allow the T-cells to attach themselves to the specific regions on cancer cell membranes where the membranes of both cells are manipulated and pulled. This allows the T-cells to stretch and bend the cancer cell membranes making it easier for perforin to work. But, this can only happen if membranes are moulded in the right direction.
Preference for outward curved cell membranes
The researchers found that perforin preferentially punctured cell membranes curved from outside rather than inside. They believe that this bias ensures that the killer proteins reach the intended targets within the cancer cells. Further, it could protect the T-cells from self-destruction.
Image Credits: Wikimedia
Analysing the physical properties of cells
According to the researchers, most experiments relied on drug-target interaction (biophysical assay) between cancer cells and T-cells extracted from healthy and affected blood donors on a molecular level. They used highly advanced microfluidic pumps, micropipettes and AI-powered manipulators, which could maintain pressure independently.
“This technique really allows us to tease apart the whole integrated process because it is such a controlled method. One micropipette picks up a T cell, and another picks up a tumour cell, and we bring them into contact on a microscope.”
“We image the entire cytotoxic process. At the same time, because we control and know the exact pressure inside each of the micropipettes, we can also measure the mechanical properties of the cells as they are interacting and engaging in the process,” said Mate Biro, study author.
This study significantly contributes to our current understanding of how T-cells interact with the disease-causing organisms and destroys them. Knowing that mechanical forces within T-cells help perforin to puncture cancer cell membranes could allow researchers to understand how perforins and similar proteins work at the microscopic level.
The study was published in the journal Developmental Cell.
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