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The newspaper of The Johns Hopkins University March 20, 2006 | Vol. 35 No. 26
Newly Discovered, Multitasking Killer Cells Fights Cancer

By Vanessa Wasta
Johns Hopkins Medicine

A mouse immune cell that plays dual roles as assassin and messenger, normally the job of two separate cells, has been discovered by an international team of researchers from the United States and France. The discovery has triggered a race among scientists to find a human equivalent of the multitasking cell, which could one day be a target for therapies that seek out and destroy cancer.

"In the same way that intelligence and law enforcement agencies can face deadly threats together instead of separately, this one cell combines the ability to kill foreign pathogens and distribute information about that experience," said Drew Pardoll, the Seraph Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, whose findings are reported in the February issue of Nature Medicine. "We think this hybrid cell speeds up immune reactions and makes the system more efficient."

The Johns Hopkins investigators speculate that the hybrid, dubbed IKDC for interferon-producing killer dendritic cell, has been missed by cancer biologists because it is rare, making up one-10th of cells in the spleen with similar features, such as other dendritic cells, according to Frank Housseau, research associate at the Kimmel Cancer Center and member of Pardoll's immunology laboratory.

Most of the immune system typically works through a web of cross talk and signaling among a variety of cells. One of the first immune cells that invading bacteria or cancer cells, both of which carry antigens that alert the immune system, may encounter is a natural killer cell. As the name implies, NK cells deliver a deadly blow by poking holes in the invader's outer membrane. Then NK cells secrete molecules that reach other immune cells, including dendritic cells, known as the main messenger for the immune system. Dendritic cells spread "look here" information about foreign invaders to other immune cells but do not actually kill the invaders.

It was while investigating a particular type of dendritic cell that Housseau noticed the outer membranes of these cells were studded with what were supposed to be hallmarks of NK cells--a discovery akin to finding feathers on a dog.

"We thought we were looking at dendritic cells, but we were wrong; they were some type of NK-dendritic cell blend," Housseau said. The blended cell turned out to be a newly identified actor on the immune system stage that retains all the molecular characteristics of both NK and dendritic cells.

Probing further, Housseau scoured the surface of IKDCs to create a sketch of its molecular profile. He found that it produces both types of interferon proteins, normally secreted independently by NK and dendritic cells. He also found both NK and dendriticlike molecules on the surface of IKDCs. Housseau calculated that they account for about 10 percent of conventional dendritic cells in the spleen.

IKDCs begin their lives behaving like an NK cell. After the cell encounters a pathogen, the cell switches roles from killer to dendriticlike messenger and, according to the researchers, the swap occurs only once. Then the cell dies and is replenished by the bone marrow.

"When an IKDC cell switches to its messenger function, the transformation is quite astonishing," Pardoll said. The cell sprouts long hairy tentacles called dendrites. It uses its "arms" to increase the amount of surface area it reaches to communicate and interact with other immune cells.

In the next step of their investigation, the scientists tracked the location of fluorescent-tagged IKDCs and their corresponding stage of transformation after infecting mice with bacteria called listeria. In assassin mode, the IKDCs were found in the blood and lining of the gut, liver and other organs, all areas where there is close contact with environmental pathogens. "Here, IKDCs are ready to sense invaders and spring into action," Housseau said.

Then, the group tracked the cells to the main messenger center of the immune system, the lymph nodes. Here they found approximately 35 percent of the original group of IKDCs now secreting communication molecules signaling a switch to messenger mode.

Simultaneously, Housseau's colleagues in France, led by Laurence Zitvogel at the Institut Gustave Roussy, tested whether IKDCs are culprits in killing cancer by injecting mice with a cancer drug called Gleevec, which blocks an abnormal protein produced by cancer cells, and a growth factor for NK cells. The drug-growth factor combo served as a lure, leading the IKDCs to tumors implanted in the mice. The results were that tumors shrank in mice that had received injections of IKDCs but not in those receiving conventional NK cells only. Evidence from the shrunken tumors revealed certain "cell-killing" proteins that could be traced to IKDCs. These results are published separately in Nature Medicine.

Housseau's group is conducting further studies to verify the role of IKDC cells in infection and cancer. Meanwhile, the group is profiling IKDC genes to find a specific marker that could help them identify a human counterpart.

The Johns Hopkins research was funded by the National Institutes of Health, the Janney Fund and the Seraph Foundation, and by gifts from Bill and Betty Topecer and Dorothy Needle.

Participants in the research are Camie W. Chan, Emily Crafton, Hong-Ni Fan, James Flook, Kiyoshi Yoshimura, Mario Skarica, and Monique F. Stins, all from Johns Hopkins; Dirk Brockstedt and Thomas W. Dubensky, from Cerus Corp.; and Lewis L. Lanier, from the University of California, San Francisco.


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