Researchers identify killer T cells that target and destroy cancer

T cells cling to diseased target cells and form a tight bond between them, called the “cytotoxic immunological synapse”. (Source: Creative Commons)

As part of our immune defenses, cytotoxic T cells – or killer T cells – seek out and destroy infected or cancerous cells. This process is necessary to protect the body from disease.

These specialized immune cells are armed with lytic granules containing two key components for immune attack: perforin (proteins that punch holes in target cells) and granzymes (which gain access through those holes and eventually kill disease-causing cells).

T cells cling to diseased target cells and form a tight bond between them, called the “cytotoxic immunological synapse”.

A research team from EMBL UNSW Australia in Sydney at the School of Biomedical Sciences found that the mechanical forces generated by T cells affect how effectively perforin can pierce tumor cell membranes. In an article published today in Developmental Cell, they describe cellular interactions and the integration of forces both in front of and behind the cell.

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The researchers found physical forces within T cells that propel lytic granules to the immunological synapse, where their payload is released. These forces also allow T cells to take over sections of the cancer cell membrane where the membranes of both immune cells and target cells are stretched and manipulated.

“It was very interesting to find that, in addition to mechanical stress and biochemical configuration, the shape of the target cell membrane plays an important role in T-cell-mediated killing of cancer cells,” said Dr. Darian Kempe of UNSW Medicine & Health, co-author of the study. – led the research.

By stretching and bending the tumor cell membranes in a certain direction, the T cells facilitated perforin penetration, but only if the membranes were bent in the right direction.

T cells (blue) cling to cancer target cells (orange) and generate killing forces with pore-forming proteins (yellow). (PREDICTION: James Cremasco, Darian Kempe and Mate Biro)

Shift towards outwardly curved cell membranes

Using human melanoma cell lines, the researchers demonstrated that perforin preferentially perforates outwardly curved tumor cell membranes rather than inwardly curved ones. The authors believe that this bias ensures that the killer payload is delivered to its intended recipient, and may also be another layer of protection for T cells from their own attack.

“As the granules arrive, their contents will be emptied in this region of the membrane, which is very strongly curved. The shift between positively curved and negatively curved membranes was completely unexpected,” said Australian EMBL team leader Associate Professor Mate Biro of UNSW Medicine & Health, who was senior author and team leader.

T cells shorten their tail to propel lytic granules forward towards the nucleus. (CREDIT: Cellular)

Measurement of mechanical properties of cells

A/prof. Mate Biro said most of the experiments were based on subtle biophysical analyzes with cancer cell lines and T cells isolated from healthy blood donors and mice. They used high-precision microfluidic pumps, computer-controlled micromanipulators, and micropipettes in which the pressure could be controlled independently.

“This method really allows us to separate the whole integrated process because it is a very controlled method. One micropipette picks up the T cell and the other picks up the tumor cell, and we put them together under a microscope.

“We visualize 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 interact and participate in the process,” said A/Prof. Biro.

This research contributes to understanding the fundamental mechanisms involved in how T cells destroy disease-causing or diseased cells in our bodies. Knowing that mechanical forces are also at work when pore-forming agents such as perforin pierce target cells could also help researchers study how these proteins work at the molecular level.

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Note: Materials provided above by the University of New South Wales. Content can be edited for style and length.

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