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
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
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
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
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
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
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
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