Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Understanding Natural Killers Could Lead to New Hepatitis Treatments

05.04.2005


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.

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.


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.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>