Navigation Links
How killer immune cells avoid killing themselves

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.

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 [in which it was synthesized]."

The real danger zone for the cell when it comes to perforin is the ER, Voskoboinik explained. Conditions there should be ideal for perforin to work, but something keeps it from doing so. The new study links that protection to a single amino acid at one end of the perforin protein. When that amino acid is substituted with another, perforin doesn't make it to the Golgi compartment, it builds up in the ER, and the cell dies.

"Perforin goes from zero to extremely high levels within 24 hours and it has everything it needs to be functional," Voskoboinik said. "The cell relies on a really efficient transport system to move perforin away from the danger zone and as a result the cell is absolutely protected."

The findings "close a chapter" in our understanding of the immune system that has existed in the field since perforin was discovered almost 25 years ago, Voskoboinik says. "It was one of those things that was out there on Olympus untouched. Everyone would just stare at it. That's what got us interested."


Contact: Elisabeth Lyons
Cell Press

Related biology news :

1. Scientists track evolution and spread of deadly fungus, one of the worlds major killers
2. NOAA scientists find killer whales in Antarctic waters prefer weddell seals over other prey
3. Natural (born) killers: What do they really do?
4. Killer paper for next-generation food packaging
5. Monitoring killer mice from space
6. Killer paper for next-generation food packaging
7. Virus killer gets supercharged
8. Battling a bat killer
9. Ants found to use multiple antibiotics as weed killers
10. Experts identify biological control to contain fungus killer in Kenyas maize supply
11. Plant disease -- more than a crop killer
Post Your Comments:
(Date:11/17/2015)... , Nov. 17, 2015  Vigilant Solutions announces today ... its Board of Directors. --> ... recently retiring from the partnership at TPG Capital, one ... with over $140 Billion in revenue.  He founded and ... all the TPG companies, from 1997 to 2013.  In ...
(Date:11/12/2015)... LONDON , Nov. 11, 2015   ... and reliable analytical tools has been paving the ... and qualitative determination of discrete analytes in clinical, ... sensors are being predominantly used in medical applications, ... and environmental sectors due to continuous emphasis on ...
(Date:11/9/2015)... 2015  Synaptics Inc. (NASDAQ: SYNA ), the ... entry into the automotive market with a comprehensive and ... of consumer electronics human interface innovation. Synaptics, industry-leading touch ... the automotive industry and will be implemented in numerous ... , Japan , and ...
Breaking Biology News(10 mins):
(Date:11/26/2015)... , England , November 26, 2015 ... Lightpoint Medical, an innovative medical device company specializing in imaging ... grant from the European Commission as part of the Horizon ... the company to carry out a large-scale clinical trial in ... -->      (Logo: , --> ...
(Date:11/25/2015)... and HOLLISTON, Mass. , Nov. ... (Nasdaq: HART ), a biotechnology company developing bioengineered ... Jim McGorry will present at the LD ... 2015 at 2:30 p.m. PT. The presentation will be ... 30 days. Management will also be available at the ...
(Date:11/25/2015)... 2015 The Global Genomics ... professional and in-depth study on the current state ... ) , The report ... definitions, classifications, applications and industry chain structure. The ... markets including development trends, competitive landscape analysis, and ...
(Date:11/24/2015)... , Nov. 24, 2015 Halozyme Therapeutics, Inc. (NASDAQ: ... Conference in New York on Wednesday, December ... Helen Torley , president and CEO, will provide a corporate overview. ... New York at 1:00 p.m. ET/10:00 a.m. PT . ... investor relations, will provide a corporate overview. --> th ...
Breaking Biology Technology: