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April 05, 2005
Understanding Natural Killers Could Lead to New Hepatitis Treatments
Researchers have discovered that natural killer T (NKT) cells, the
immune system's sentinels, patrol the labyrinthine blood vessels of the
liver for invaders or signs of tissue damage and demonstrate a dogged
behavior not seen before in other T cells.
The new studies show that NKT cells crawl along vessel walls, even
upstream against blood flow. They halt only when they receive a
chemical signal to unleash an immune-system assault on marauding
microbes, other invaders or damaged tissue.
“In general, these NKT cells could have an important inflammatory role, particularly in the case of chronic hepatitis.”
Dan R. Littman
The findings offer a new way of thinking about this important class
of immune cell, which is responsible for the inflammation and cell
death in the liver due to hepatitis. Hepatitis can be a reaction to
viruses, parasites such as malaria or other infections. Learning to
“call off” the NKT cell's pursuit and attack could offer a
treatment for hepatitis and associated complications.
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The following video shows natural killer T cells (illuminated by green fluorescent protein)
patrolling the blood vessels of the liver. Watch Video
2.2MB QuickTime Movie
(requires QuickTime Player)
Image: Michael Dustin, NYU
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The researchers, led by Dan Littman, a Howard Hughes Medical
Institute investigator at New York University (NYU) School of Medicine,
published their findings online on April 5, 2005, in the Public
Library of Science Biology. Lead authors on the paper were
Frederick Geissman in Littman's laboratory and Thomas Cameron in the
laboratory of co-author Michael L. Dustin, also of NYU. Other
co-authors were from the La Jolla Institute for Allergy and Immunology
and Millennium Pharmaceuticals in Cambridge, Mass.
Although it was known that NKT cells were more prevalent in the
liver than in any other organ, said Littman, it was not known how they
accomplish the Herculean task of immune surveillance in the liver. The
liver detoxifies and removes waste products from the blood. Inside the
liver, vascular passages, or “sinusoids,” are filled with a
witches' brew of nutrients, toxins, proteins, lipids and other
chemicals. Thus, immune guardians that patrol the liver must tolerate
many foreign molecules, yet respond readily to infection.
“It wasn't clear how NKT cells survey (tissue), or even if
they survey at all,” said Littman. To visualize the activity of
NKT cells in the liver, Geissman used mice in which NKT cells were
tagged with a fluorescent marker. This was accomplished by replacing
the gene encoding a characteristic NKT cell surface receptor called
CXCR6 with the gene for green fluorescent protein. Although the CXCR6
receptor is known to be central to the function of NKT cells, its
overall role was not known, said Littman.
Working with Geissman, Cameron adapted a technique called intravital
fluorescence microscopy that enabled them to observe in real time the
behavior of the tagged cells in the livers of mice.
“The startling discovery was that these NKT cells just move
within the sinusoids intravascularly,” said Littman. By contrast,
he said, immune cells in the lymph nodes and spleen perform their
surveillance ensconced within specialized compartments shielded from
the turmoil of the bloodstream. “In this case, it looks like NKT
cells are doing their surveillance from within the vessels,” he
said.
The observations revealed that the NKT cells crawl randomly within
the sinusoids, even against blood flow, passing one another and even
changing direction, said Littman. “It is very different from the
kind of classical mechanism of lymphocytes rolling through vessels with
the blood flow and when they are activated coming to a stop and then
crossing through vessel walls in response to a signal.”
The researchers observed that the roving NKT cells stopped their
movement when alerted by a foreign protein, called an antigen,
“We think this is a reflection of their normal function of
searching for antigen,” said Littman. “Whenever there is
detection of antigen reflecting some kind of damage or local infection,
the cell would stop in the vicinity of that signal and provide cytokine
signals that would attract other inflammatory cells that destroy the
invading microorganism and may also facilitate repair of the
damage.”
In other experiments, the researchers explored the role of the CXCR6
receptor in the NKT cell's behavior. Receptors are protein sensors that
nestle in the membranes of cells and detect external signaling
molecules called ligands. When ligands are bound by the receptor, a
specific chemical signal is transmitted to the interior of the
cell.
In the case of NKT cells, the researchers found that the mice
genetically rendered deficient in CXCR6 showed reduced survival of
their NKT cells, but no change in the speed or pattern of their
patrolling. The studies showed that the presence of CXCR6 prolonged the
NKT cells' survival. The researchers also found that the NKT cells of
CXCR6-deficient mice showed a reduced patrolling, as well as a
decreased severity of artificially induced hepatitis.
“So, all the evidence we can obtain so far points to CXCR6
being involved in promoting survival of these NKT cells when they get
into the environment of the liver, and that's how the cells tend to
accumulate there,” said Littman. “Our data don't support a
critical role of CXCR6 in crawling behavior of the cells.”
Evidence for the role of CXCR6 in the survival of NKT cells — as
well as the cells' involvement in triggering hepatitis — suggests a
possible clinical implication of the findings, said Littman. “In
general, these NKT cells could have an important inflammatory role,
particularly in the case of chronic hepatitis,” he said.
“If that is the case, we speculate that it may be possible to
manipulate the NKT cell, perhaps by interfering with CXCR6 function, to
ameliorate the inflammatory process,” he said.
Still unknown, said Littman, is which antigens alert NKTs to
infections, as well as the nature of the regulatory machinery of
crawling and stopping. The chemical the researchers used in their
experiment is a general immune activator and does not reflect what
occurs during an actual infection, he noted. Such knowledge would offer
important insights into the mechanism of inflammation and liver damage
due to infections, he said.
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Versión en español
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