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 Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

New cellular pathway helps explain how inflammation leads to artery disease

22.06.2018 | Life Sciences

When fluid flows almost as fast as light -- with quantum rotation

22.06.2018 | Physics and Astronomy

Exposure to fracking chemicals and wastewater spurs fat cell development

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>