How killer immune cells avoid killing themselves

ScienceDaily (June 9, 2011) — After eight years of work, researchers have unearthed what has been a well-kept secret of our immune system's success. The findings published online on June 9th in Immunity, a Cell Press publication, offer an explanation for how specialized immune cells are able to kill infected or cancerous cells without killing themselves in the process.

See Also:Health & MedicineImmune SystemLymphomaStem CellsBrain TumorLung CancerNervous SystemReferenceNatural killer cellT cellImmune systemWhite blood cell

The focus of the study is a molecule known as perforin, whose job it is to open up a pore in cells targeted for destruction. With that pore in place, proteases known as granzymes can enter target cells and destroy them.

Perforin is one of the most critical ingredients for a functional immune system. Without it, mice succumb to viral illness and lymphoma. Humans born without a working perforin gene develop an aggressive immunoregulatory disorder in the first few months of life and usually die unless treated with cytoxic drugs or a bone marrow transplant.

But perforin itself is an incredibly destructive molecule. "Perforin forms a massive pore," said Ilia Voskoboinik of the Peter MacCallum Cancer Centre in Australia. "It allows almost any protein to diffuse into a target cell. A few hundred molecules of perforin is sufficient to obliterate any cell."

When the immune cells known as cytotoxic lymphocytes (including cytotoxic T lymphocytes and natural killer cells) are activated, "they produce a massive amount of perforin, yet the cells are fine," Voskoboinik said. The question was: how do our immune cells manage such toxic cargo without endangering themselves?

Before perforin is released, the cells that produce it have to transport it from one part of the cell to another. That transport chain starts in a component of the cell known as the endoplasmic reticulum (ER). From there, it moves to the Golgi and into secretory granules where it is packaged together with granzymes. It is those secretory granules that ultimately fuse with the plasma membrane of the cytotoxic cell and allow its release into the junctions between the immune cell and the cell it aims to kill.

Scientists used to think perforin had an inhibitory domain within its structure that was only removed once they were safely stored in the secretory granules. (The acidic environment within secretory granules keeps perforin inactive until its release.) But Voskoboinik's team purified perforin and found that the protein was always active regardless of whether they had removed the supposed inhibitory domain or not.

"It seeded doubt about how perforin is inhibited," he says. "It was a puzzle. Perforin was fully functional but for some reason it couldn't kill the cell