(Monterotondo, Italy) Nearly fifty years ago, researchers discovered that when cells in laboratory cultures are infected by a virus, they secrete a substance that protects other cells from infection. In 1957 Alick Issaks and Jean-Jacques Lindenmann traced this effect to a protein called interferon, a molecule now known to play a key role in the immune system. Human and animal cells produce it in a rapid “first wave” response to infections. Since its discovery, scientists have sought to use this natural substance to cure all sorts diseases, and clinical trials have demonstrated interferon’s potential to combat diseases as different as hepatitis C, blood cancers, and multiple sclerosis. Yet many aspects of interferon biology remain a mystery – including what initially prompts the body to produce it. Now Ulrich Kalinke and Winfried Barchet at the European Molecular Biology Laboratory (EMBL) station in Monterotondo, Italy, have identified specific cells in the body able to launch a massive, initial round of interferon production. Their work, reported in the current issue of the Journal of Experimental Medicine, is changing how researchers think of the interferon system and adds a key element to our understanding of how the immune system works.
Interferons have the ability to put the cell on ”hold”; they slow down a lot of processes that would otherwise help viruses reproduce very quickly. While many deadly viruses have evolved the means to evade these measures, most are slowed down enough for other phases of the body’s immune system to kick into high gear and eradicate them. Animals that are born without the ability to mount an interferon defense are unable to survive even mild infections and they quickly die.
Until now, scientists have generally believed that the body produces most of its interferon through a sort of “feedback loop”: special proteins called receptors, on the surface of the cell, sense a few “starter” interferon molecules, and this activates a machinery that churns out vast amounts of different types of interferons. These spread through the body as an alarm signal. Studies of infection in cell cultures suggested that removing the receptors, and thus the “sensing apparatus,” also halted the interferon-production machinery.
“But those experiments primarily used one specific kind of cell,” Kalinke says. “Because just about any type of cell starts producing interferon when you stimulate it, not many scientists were motivated to look for specific cells that might produce the majority of IFN in an organism."
Comparing normal mice to those whose cells didn't have interferon receptors, the researchers discovered a puzzling fact. Within a few hours of the onset of an infection, they found that levels of interferon rose dramatically in the blood of both types of mice. This couldn’t be due to a feedback mechanism, Kalinke reasoned, so somewhere in their bodies, mice must have cells that produce massive quantities of the protein very quickly after virus appears.
He convinced PhD student Winfried Barchet to undertake a search for “interferon-producing cells”, or IPCs. It was obviously an exciting experiment to try – EMBL’s Director General Fotis C. Kafatos told Barchet he was holding onto a “nugget of gold.” But the scientists were nervous. “The evidence was out there for everybody to see,” Barchet says. “There was a real danger of getting scooped on the story.”
However, Barchet and Kalinke found themselves in a unique position to track down the IPCs. The laboratory in Monterotondo, which is an external unit of EMBL’s headquarters in Heidelberg, specializes in mouse biology. It also has what Kalinke calls the “Virus Suite,” a set of activities that make it possible to study infectious diseases in both animals and cell cultures.
They began their search for the IPCs in the spleen – an organ which is heavily involved in the body’s immune reactions. Experiments performed by collaborator Bernhard Odermatt marked interferon in a purple color and helped them zoom in on a “hot zone”: an area of the spleen called the marginal zone.
But here they ran into problems. “This region contains a large number of different types of cells, all mixed very closely together,” Barchet says. “You can’t distinguish them in tissue sections under the microscope. So we approached the group of Marina Cella and Marco Colonna in Basel, who have very sophisticated equipment that can ‘sort’ cells. We were able to pin early IFN production down to a very specific type called a dendritic cell.”
This finding was intriguing because dendritic cells are major players in the “second wave” of the body’s immune response. Whereas interferon acts as a sort of a generic weapon that will attack nearly any type of virus, the body has a backup system recognizing antigens, the unique molecular “fingerprints” of pathogens like viruses and bacteria. Dendritic cells acquire these unique markers, activate immune cells, and thus are able to kick off this "second wave" immune response.
“Researchers have been looking for a connection between the first-round, ‘innate’ immune system, which involves interferon, and the ‘adaptive’ or second-round immune system,” Kalinke says. “It’s obviously exciting to find a type of cell known to participate in one system playing an important role in the other. But there are several sub-types of these cells, and we aren’t yet sure whether the dendritic cells that produce interferon can also acquire viral antigens.”
Dendritic cells can be found in many places in the body, and now Kalinke and Barchet will go looking for IPCs elsewhere. “An obvious place to look is in the lungs or in other parts of the body that are first exposed to viruses,” Barchet says.
IPCs probably play a major role at the very beginning of an infection; after several hours, most interferon is probably produced through the activation of the feedback mechanism. But the discovery of IPCs may be useful in the search for medical applications for interferon. “Ever since their discovery, people have been interested in medical applications based on these molecules,” Kalinke says. “But it has taken many years for basic research to show us the mechanisms by which they really operate. Now we’re starting to understand the real biology, which is exciting renewed interest in the innate immune response.”
short version
(Monterotondo, Italy) Nearly fifty years ago, researchers discovered that cells infected with viruses secreted a protein called interferon which could protect other cells from infections. Now scientists at the European Molecular Biology Laboratory (EMBL) station in Monterotondo, Italy, have identified specific cells in the body able to launch a massive, initial round of interferon production. Their work, reported in the current issue of the Journal of Experimental Medicine, is changing our understanding of the interferon system and adds a key element to our understanding of how the immune system works.
In clinical trials, scientists have sought to use this naturally-produced protein to combat diseases like multiple sclerosis, hepatitis C, and blood cancers. Yet many aspects of interferon biology have remained a mystery - including what initially prompts the body to produce it. In cell cultures, almost any type of cell can be stimulated to produce interferons. Until now, most scientists have thought that the body mostly produces the substance in a “feedback loop”: cells sense a few “starter” interferon molecules, and this activates a machinery that produces heavy amounts of the protein.
In studies of mice, Ulrich Kalinke and Winfried Barchet found large amounts of interferon even in the blood of animals whose cells can’t activate such a feedback loop. This suggested that somewhere in the mouse body were cells that produced an initial, heavy dose of the protein. They were able to trace interferon production to a particular type of cell in the spleen called dendritic cells, which are known to be involved in other types of immune responses. Their work has implications for future therapies based on interferon.
Virus-induced Interferon-alpha Production by a Dendritic Cell Subset in the Absence of Feedback Signaling In Vivo. Winfried Barchet, Marina Cella, Bernhard Odermatt, Carine Asselin-Paturel, Marco Colonna, and Ulrich Kalinke. J. Exp. Med. Volume 195, Number 4, February 18, 2002 1–11. http://www.jem.org/cgi/content/full/195/4/1
Ulrich Kalinke, Ph.D.
Head of the Department of Immunology
Paul-Ehrlich-Institute
Paul-Ehrlich-Str. 51-59
D-63225 Langen, Germany
Phone +49-6103-772002/3
Fax +49-6103-771253
E-mail kalul@pei.de
By: Russ Hodge
Journal
Journal of Experimental Medicine