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Deadly instincts Natural killer cells respond rapidly to viral protein By Darrell E. Ward
The team found that these natural killer (NK) cells are wired to detect a unique protein on the surface of infected cells. The protein activates NK cells, which then attack and destroy the infected cells within six hours. The research also led investigators to what may be a cache of viral stealth weaponry and a new strategy for treating cancer. "Our findings provide a glimpse of what triggers NK cells early in a viral infection, something that has been poorly understood," says study leader Wayne M. Yokoyama, M.D., the Sam J. Levin and Audrey Loew Levin Professor of Research in Arthritis, professor of pathology and immunology, and investigator of the Howard Hughes Medical Institute. "We found that a sizeable proportion of NK cells respond to this viral protein within hours, far faster than the several days it takes the other and larger body of immune killer cells, called T cells, to mount a response." NK cells, explains Yokoyama, are the immune system's initial strike force that works to hold off the invading virus until the army of T cells can be mustered to fight and control the infection. In addition, NK cells are known to recognize and destroy certain kinds of tumor cells and to play a role in bone marrow transplant rejection, says Yokoyama, who also is a member of the tumor immunology program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. Yokoyama's team studied mice infected with murine cytomegalovirus (MCMV). In research published last year in the journal Science, the Yokoyama group found that NK cells detect MCMV-infected cells using a molecular detector -- a receptor -- on their surface. Mice with NK cells that lacked the receptor were unable to control the virus and died. "The earlier study revealed that a particular activation receptor is involved in protection by NK cells," says Yokoyama. "Now we've discovered what that receptor sees." To verify that the protein, known as m157, causes NK cells to destroy infected cells, the investigators transferred the protein into a line of tumor cells not normally recognized by NK cells. The immune cells killed the tumor cells. "Perhaps someday we can exploit this ability and harness the power of NK cells to eradicate tumors or control other kinds of infections," says Yokoyama. The investigators also found that m157 originates in the virus and not in the infected cell. For clues about the function of the protein, they used a special computer program that predicts the final shape of the protein based on its sequence of amino acids. To the researchers' surprise, the protein appeared to mimic the shape of a cellular molecule known as major histocompatibility complex (MHC) class I. The virus also had 12 other proteins that mimic MHC class I molecules. MHC class I molecules are molecular flags that tell immune cells whether cells in the body are healthy or infected. The molecules that mimic MHC class I, including m157, also are produced by the MCMV-infected cell for the virus and presumably are displayed on the cell's surface. "The question is what do these molecules do for the virus?" says Yokoyama. "Are they also detected by NK cells, or are they involved in evading the immune system?" To date, the only known function of such molecules is to help viruses evade detection by T cells, he explains. The discovery that MCMV has so many molecules that mimic MHC class I suggests that the immune system may use receptors on NK cells as a general mechanism to respond to certain viruses. "Perhaps there are proteins like m157 in other viruses that are detected by related kinds of receptors in the body," says Yokoyama, "not only in mice but perhaps in humans as well." The findings are described in the June 25 issue of the Proceedings of the National Academy of Sciences. |
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