May 18, 2005 A gene that signals a yeast cell to make bread rise and mice to eat a better diet also helps selectively silence the immune system, researchers have found.
The finding may help explain how a mother avoids rejecting a genetically foreign fetus and provides a new target for treatments to help the immune system ignore other desirables like a transplanted organ.
“Think of this like a radio transmitter and a receiver,” says Dr. David H. Munn, pediatric hematologist-oncologist at the Medical College of Georgia and lead author of the study in the May issue of Immunity.
The transmitter is indoleamine 2,3-dioxygenase, or IDO, an enzyme particularly expressed in places such as the gastrointestinal tract and tonsils where the immune system routinely meets up with foreign substances it might want to ignore.
Drs. Munn, Andrew L. Mellor and Simon J. Conway published a Science article in 1998 showing IDO’s role in protecting the fetus from rejection by the mother’s immune system during pregnancy. Later they learned that tumors and persistent viruses such as HIV may hijack this mechanism to shield themselves from immune attack.
They knew IDO degraded tryptophan, an amino acid essential to the survival of T cells. They weren’t so certain what happened at the receiving end.
The researchers wondered if T cells exposed to IDO might simply starve to death without enough trytophan, one of nine essential amino acids attainable only through food. “If the T cells are just starving, then you don’t need a receiver. They just die. But the T cells didn’t seem to be dying. They seemed to be rendered selectively non-responsive,” says Dr. Munn. “That sounded more like the T cell was participating in this process.”
So the researchers started looking at the few genes known to respond to amino acid levels and found GCN2.
GCN2 is present and active in many cells, but its major sites of action are unknown and its role in T cells was unexplored, Dr. Munn says. “GCN2 is a nutrition sensor in yeast,” says Dr. Munn. GCN2 helps yeast know when it has sufficient nutrition to grow; bread keeps rising until yeast run out of nutrition. A paper published in March in Science explores GCN2’s role in mammalian survival by enabling mice to sense they need to eat a well-balanced diet to stay healthy.
Dr. Munn contacted Dr. David Ron, a professor of medicine and cellular biology at New York University School of Medicine’s Skirball Institute, studying the nutritional aspects of the gene. Dr. Ron, a co-author on the Immunity paper, shared a GCN2 knockout mouse he developed and helped the MCG researchers study the gene’s role in T cells.
When these knockout mice were exposed to IDO, their T cells simply ignored it.
The researchers had found a receiver and possibly more.
“No one had known any gene specifically targeted by IDO, and now we have one,” says Dr. Munn. “We had not known how T cells were turned off. We didn’t know if the T cells just were never activated, or if they were actively suppressed by IDO. They all look like resting T cells. Now we do know that there are differences.”
MCG researchers want to know more about how GCN2 puts T cells to sleep. “Whatever it’s doing doesn’t appear to be killing the T cells. It would be nice to be able to mimic the effect of IDO by using a drug that activates this pathway.” Now that they have a knockout, comparative studies with regular mice can determine other genes that might be impacted downstream of GCN2.
Another big question is whether T cells deactivated by this system can be reactivated. Knowing the role of the GCN2 gene makes it easier for scientists to watch what happens to the T cells affected by IDO in a living organism.
“We know that IDO itself is an important pathway. Evidence is emerging that IDO seems to contribute to several important regulatory processes in the immune system,” Dr. Munn says of findings from labs across the country. “But there has been a question in the field about how the IDO expressed in one cell can signal to neighboring T cells. Here’s our first evidence of one way it may do so. By giving you a target in the T cell that IDO is talking to, it helps you understand the system better and we think it also may give us another target for drugs to try to intervene in the system.”
The studies were funded by the National Institutes of Health and the Carlos and Marguerite Mason Trust.
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