Researchers at the University of Toronto and Mount Sinai Hospital have identified a protein that plays a critical role in the regulation of "natural killers cells" in the immune system's battle against foreign and diseased cells.
"Our research is a small part of the larger problem of how viruses and diseased cells ravage the body and circumvent our immune system," says Kathleen Binns, a U of T doctoral student in medical genetics and microbiology and an author on a paper in the June 20 issue of Science.
Using mass spectrometry, Binns, who does research in the Samuel Lunenfeld Research Institute at Mount Sinai and MDS Sciex, sequenced and identified a mystery protein from co-researchers at the Swiss Federal Institute of Technology in Switzerland.
Once identified, the protein (SSPase) was sent back to the Swiss researchers where they cloned its gene and sequenced its DNA. That gene, they discovered, is a key component involved in regulation of "natural killer cells" - cells produced by the body's immune system that attack foreign or mutated cells like caused by viruses or cancer.
"This research gives us a better understanding of how the immune system works. As a result, we have a better understanding of how viruses and cancer try to get around this process. One day, we will hopefully be able to develop treatments and therapies to counter these rogue cells," says Binns.
A group of genes called the major histocompatibility complex I (MHC-I) are a natural part of the immune system and present in most cells in the body, explains Binns. Acting like an information relay, the MHC-I molecules retrieve bits and pieces of the proteins from inside the cell and display them on the cell surface. "MHC complexes essentially give a read out of what's inside the cell," she says.
T-cells, one of the main components of the immune system, "examine" the protein fragments on the cell surface and if they recognize them, the T-cells move on. If, however, the T-cells do not recognize the fragments, the cell may be hosting a virus or manufacturing mutant proteins (as in the case of cancer). The T-cells then react by attacking and killing the "diseased" cells.
Some virus and tumor cells, however, have evolved mechanisms that circumvent the T-cell attack by stopping MHC production and the display of disease proteins, says Binns.
As a countermeasure, the researchers found that the immune system developed a monitor that employs the SSPase protein and uses a second type of immune cell known as a natural killer cell, she notes. The protein processes MHC-I molecules to make a peptide signal. If sufficient levels of the MHC-I protein are present in the cell, the natural killer cell moves on. If, however, the killer cell detects insufficient levels of the MHC-I protein because it has not received the particular peptide signal, the killer cell attacks and destroys the suspect cell.
"This process is a check on viruses and abnormal cells that try to bypass the T-cell system," says Binns. "Viruses become smarter, our immune systems work to counteract them and the viruses get smarter again. There's this constant evolution for the drive to survive, and viruses and cancer cells have the same drive to survive that we do."
Binns conducted the research with Andreas Weihofen, lead author on the study, Marius Lemberg and Bruno Martoglio of the Institute of Biochemistry at the Swiss Federal Institute of Technology, and Keith Ashman, an investigator at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital.
This research was funded by the Natural Science and Engineering Research Council of Canada and MDS Sciex, the Swiss Federal Institute of Technology and the Swiss National Science Foundation.
Department of Medical Genetics and Microbiology
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