Immune cells kill foes by disrupting mitochondria 2 ways

May 15, 2008

When killer T cells of the immune system encounter virus-infected or cancer cells, they unload a lethal mix of toxic proteins that trigger the target cells to self-destruct. A new study shows T cells can initiate cellular suicide, also known as programmed cell death or apoptosis, by a previously unrecognized pathway that starts with the destruction of a key enzyme in mitochondria, the power plant of the cell.

The study, from the lab of Judy Lieberman, a senior investigator at the Immune Disease Institute and Professor of Pediatrics at Harvard Medical School, reveals that T cells use both the novel pathway and the classical apoptotic pathway to interfere with mitochondrial function and induce cell death.

“This work gives us a new understanding of a major T cell defense pathway,” Lieberman says. The results will appear in the May 16 issue of Cell.

The Lieberman lab studies cytotoxic T lymphocytes (CTLs), key cells in the immune defense against viral infection and cancer. When CTLs recognize an infected or transformed target cell, they release the contents of cytolytic granules onto the target cell. These granules contain serine proteases called Granzymes, which induce programmed cell death in the target cells. Two major Granzymes, A and B, account for most of the killing activity in granules.

Granzyme B triggers the classical programmed cell death pathway involving breakdown of the outer mitochondrial membrane, and the release of death-promoting proteins which activate the caspase protease cascade and result in massive DNA damage.

Previous work from the Liebeman lab showed that Granzyme A initiates cell death by a different biochemical pathway. That pathway involves the mitochondria, but does not result in mitochondrial membrane breakdown or caspase activation, and triggers a different type of DNA damage. The current study was aimed at understanding how Granzyme A kills cells.

To identify Granzyme A target proteins in mitochondria, Lieberman and colleagues used proteomics to look at the fate of a large number of mitochondrial proteins after Granzyme A exposure. One protein, NDUFS3, a subunit of the large multi-protein Complex I assembly that participates in energy generation for the cell, disappeared.

Further work established that when Granzyme A was released into a cell, it could enter the mitochondria where it degraded NDUFS3. Further, the investigators showed that loss of NDUFS3 caused mitochondria to produce damaging reactive oxygen, known to be essential for Granzyme A’s deadly effects on cells. Destruction of NDUFS3 was sufficient to initiate the toxic effects of Granzyme A on human cells, they showed.

The new demonstrate that while both Granzymes target mitochondria, they do so in very different ways. Lieberman says she is not surprised that immune cells have multiple means of inducing mitochondrial-dependent cell death. “Many viruses and cancers have found ways to be resistant to the caspase-dependent apoptosis pathway triggered by Granzyme B, so it makes sense that immune cells would have a second, parallel pathway to cause cell death,” she said.

Source: Harvard Medical School

Explore further: Free the seed: OSSI nurtures growing plants without patent barriers

add to favorites email to friend print save as pdf

Related Stories

Static killers?

Sep 06, 2013

Mammals contain cells whose primary function is to kill other cells in the body. The so-called Natural Killer (NK) cells are highly important in defending our bodies against viruses or even cancer. Scientists ...

Discovery points way for new treatment for aneurysms

Jan 27, 2010

New research findings from a team at the Providence Heart + Lung Institute at St. Paul's Hospital and the University of British Columbia (UBC) may lead to new treatment options for abdominal aortic aneurysms (AAA) - a potentially ...

Extraordinary immune cells may hold the key to managing HIV

Dec 04, 2008

People who manage to control HIV on their own are providing scientists with valuable information about how the immune system eliminates virus-infected cells. A new study, published in the December 4th issue of Immunity, a Cell ...

Recommended for you

Plants with dormant seeds give rise to more species

16 hours ago

Seeds that sprout as soon as they're planted may be good news for a garden. But wild plants need to be more careful. In the wild, a plant whose seeds sprouted at the first warm spell or rainy day would risk disaster. More ...

Researchers successfully clone adult human stem cells

19 hours ago

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

E_L_Earnhardt
not rated yet May 16, 2008
A "KILL" is not a cure! Anything created to kill cells is likely to get into the environment and cause a pandemic!

More news stories

Researchers successfully clone adult human stem cells

(Phys.org) —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Male monkey filmed caring for dying mate (w/ Video)

(Phys.org) —The incident was captured by Dr Bruna Bezerra and colleagues in the Atlantic Forest in the Northeast of Brazil.  Dr Bezerra is a Research Associate at the University of Bristol and a Professor ...

Health care site flagged in Heartbleed review

People with accounts on the enrollment website for President Barack Obama's signature health care law are being told to change their passwords following an administration-wide review of the government's vulnerability to the ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.