This licensing process apparently helps reduce the chances that the cells will erroneously direct their firepower at the body's own tissues, according to researchers at Washington University School of Medicine in St. Louis. The process is very different from other previously identified ways that help immune cells distinguish invaders from self, and could have important implications for doctors struggling to understand such issues as persistent viral infections and patients' responses to bone marrow transplants. The findings will appear in the August 4 issue of Nature.

The immune cells in question already evoked cinematic connections simply by virtue of one of their names: scientists commonly refer to them as natural killer cells. The cells rapidly attack invaders and are continually generated in the bone marrow, leading to replacement of the entire population approximately once a week.

Scientists led by Wayne M. Yokoyama, M.D., the Sam J. Levin and Audrey Loew Levin Professor of Research in Arthritis, and professor of medicine and of pathology and immunology, discovered through experiments in mice that the arsenals of natural killer cells only become fully armed after a receptor on their surfaces interacts with a molecule on the surfaces of other cells.

The molecular details of the process were so unusual that Yokoyama and his colleagues found themselves struggling to develop terms to describe it to other immunologists.

"So many other terms that might have been appropriate--education, tolerance, instruction, selection--already have specialized meanings in immunology that really aren't appropriate for this unique process we've discovered," says Yokoyama, who is a Howard Hughes Medical Institute Investigator and chief of the Division of Rheumatology at Barnes-Jewish Hospital. "Many of these terms refer to processes with a similar outcome--improved ability to distinguish between self and non-self--but this is a very different way of reaching that goal. So we came up with the term licensing."

Their results include another ironic connection to the world of cinema spies: the molecular details of the process feature a player who is comparable to a double agent. Scientists have known for some time that natural killer cells have inhibitory receptors on their surfaces.

The natural killer cells' ability to attack is inhibited when these receptors encounter a molecule known as major hiscompatibility complex (MHC) class I on the surface of other cells. MHC serves as a kind of molecular I.D. badge, helping the natural killer cells to distinguish the self from an invader.

But Yokoyama's group found that the inhibitory receptors switch roles during licensing. Although the structure of the receptors is exactly the same in immature natural killer cells, they act not as inhibitors but as enablers. In their studies, natural killer cells in mice became much more capable of mounting attacks against invaders after they first encountered the mouse version of MHC.

"The structure of these receptors on human natural killer cells is different from the mouse version, but they have a similar function," says lead author Sungjin Kim, Ph.D., research instructor in rheumatology. "We will be looking for a way to see if the human version also participates in some kind of licensing process."

The group's research was made possible by a unique mouse line created by Ted H. Hansen, Ph.D., professor of pathology and immunology and of genetics. Mice normally have many different versions of the MHC molecule, but Hansen created a line that makes only one. This was essential to the ability of Yokoyama's group to test its hypothesis.

The new findings from Yokoyama's laboratory could explain some puzzling outcomes in the clinic, including why some patients with hepatitis C infections can be cured while others have a chronic infection for the rest of their lives.

"This could be an important advance both conceptually and in terms of clinical practice," Yokoyama says. "It could also help us match bone marrow transplants in a way that increases the immune system's ability to fight off a relapse of the leukemia."

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