December 8, 1999

HUMAN BODY'S "NATURAL KILLER" DEFENSE REVEALED

ROCKVILLE, Md.--A molecular lock and key complex of so-called natural killer cells in the blood stream has been found for the first time, scientists of the University of Maryland Biotechnology Institute (UMBI) report in today's issue of the journal Nature.

Natural killer (NK) cells are a critical, first line of defense against cancer tumor cells and cells infected with the AIDS virus and other harmful microbes. They have molecules on their cell surfaces called NK receptors that find and destroy diseased cells.

The scientists have captured the first real look at the subtle workings of NK cells, says co-author Roy A. Mariuzza, professor and molecular biologist at UMBI's Center for Advanced Research in Biotechnology (CARB) in Rockville, Md. "This tells us for the first time how NK cells recognize the difference between normal and abnormal, infected cells." He says the molecular machinery of NK cells is not as well understood as that of T or B white blood cells for fighting infections, but is also essential for maintaining health.

"Lucky for us, there are NK cells," says Mariuzza. Some viruses such as HIV, the cause of AIDS, have evolved camouflaging tricks and can't be destroyed by T cells. "The NK cells find and destroy unprotected cells that are infected, those that no longer have markers called MHC molecules on their surface to say they are healthy," he says. The NK cells patrol the bloodstream in all directions like molecular police cruisers, says Mariuzza, using their NK receptors to signal out abnormal cells without proper MHC identification. The NK cell punches the abnormal cell with toxic granules and kills it.

At CARB, Mariuzza and collaborators discovered how an NK receptor molecule locks onto MHC molecules, which are on the surfaces of practically all normal cells. Once locked on, the NK cell "knows" the blood cell with the MHC marker is all right. It unlocks, then goes "cruising" off to check out other cells.

The laboratory breakthrough occurred when the researchers made a pure crystal of the molecular complex, or the checkup point, of an NK receptor and an MHC marker molecule. They then applied a powerful beam of X-rays to the crystal to compute the positions of the atoms making up the molecular lock-and-key structure. The result was the first 3-dimensional molecular structure known for the interaction of the NK receptor and an MHC marker.

"By identifying the molecular structure, the researchers have validated the missing self hypothesis that NK cells will attack only virus-infected or tumor cells that have lost their healthy self identity," says Jennie Hunter-Cevera, UMBI president.

For medical research, the discovery helps form a more rational way of discovering new disease fighting drugs, says collaborator David H. Margulies of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Now that the first molecular structure of an NK receptor/MHC linkage is known, says Margulies, DNA researchers can experiment with "changing the molecules to assess how they bind and behave." He comments that the discovery means now "you see exactly what the NK cell sees".

Mariuzza adds, "Our results give us a basis for expanding research on NK cell receptors and MHC. We have actually found two distinct (molecular) binding sites. One was unexpected. Now we need to compare this to still unknown structures of other NK receptors to find out how each of them works."

Scientists estimate that NK cells make up five to 16 percent of the total number of white blood cells that the body uses to fight infections. People with defective or absent NK cell activity can contract a wide spectrum of diseases, particularly cancers. In fact, results from a number of clinical trials indicate that NK cells can be used to control tumor metastases, the spread throughout the body. The therapeutic uses of NK cell activity will likely increase as their relationships to healthy and diseased cells becomes better known, say the researchers.