Killer cells recognize specific viruses

St. Louis, May 4, 2001 -- Researchers have discovered that immune system cells called natural killer cells can recognize and destroy specific viruses. Scientists previously thought these cells responded to infection only in a nonspecific way.

"Understanding how natural killer cells eradicate virus-infected cells will help in the development of specific vaccines and treatments," says Wayne M. Yokoyama, M.D., a Howard Hughes Medical Institute Investigator and the Sam J. Levin and Audrey Loew Levin Professor of Medicine and chief of rheumatology at Washington University School of Medicine in St. Louis.

Yokoyama and colleagues report their findings in the May 4 issue of Science. Michael G. Brown, Ph.D., now an assistant professor of medicine at the University of Virginia, and Ayotunde Dokun, an M.D., Ph.D. student at Mt. Sinai School of Medicine are first authors of the paper. Both did the work in Yokoyama�s lab.

Natural killer cells were named for their ability to spontaneously kill cancer cells. As part of the body�s innate immunity, they also secrete a protein called interferon-gamma, which rallies the rest of the immune system against infected cells. By responding as soon as a damaged cell appears, natural killer cells defend the body while other immune cells are gearing up for action. Their radar system for detecting cells that need to be destroyed consists of a large array of related protein receptors. These activation receptors sit on the natural killer cell surface.

Scientists have suspected that natural killer cells might be able to respond in more specific ways than interferon secretion. For example, humans without natural killer cells are susceptible to only certain types of virus infections. Also, strains of mice that normally resist murine cytomegalovirus (MCMV) become susceptible when deprived of natural killer cells whereas other strains of mice are genetically susceptible. In previous work, the Yokoyama laboratory, in collaboration with a group led by Dr. Anthony Scalzo at the University of Western Australia, determined that a genetic locus, termed the NK gene complex, controlled resistance or susceptibility.

In their current work, the researchers found an unusual mouse that seemed to have the genes for resistance but the mice were susceptible. They showed that these mice had the usual complex of genes for highly related natural killer cell receptors, including a protein family called Ly-49. However, one member of that family was missing. It was a receptor called Ly-49H.

The group then inactivated the Ly-49H receptors of normal, MCMV-resistant mice by injecting an antibody that attaches only to Ly-49H protein. They injected other normal mice with an antibody that eliminates virtually all natural killer cells. When exposed to MCMV, the two groups of mice developed equally severe infections. So taking away Ly-49H was just as harmful as taking away the natural killer cells themselves.

"Without the Ly-49H receptor, the virus infection is rampant, and the mice die," Yokoyama says. "Our results suggest that natural killer cell receptors also play a role in specific defense against other infections."

Brown MG, Dokun AO, Heusel JW, Smith HRC, Beckman DL, Blattenberger EA, Dubbelde CE, Stone LR, Scalzo AA, Yokoyama WM. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science vol. 292 pp 934-937, May 4, 2001.

This research was supported by the Howard Hughes Medical Institute and by grants from the National Institutes of Health and the National Health and Medical Research Council of Australia

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