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Stanford Report, January 14, 1998

An immunologic enigma solved: 1/14/98

Natural-born killers: An immunologic enigma solved


Side-by-side research papers featured in the December issue of Immunity resolve a mystery of basic immunology while suggesting a new way to improve the success of bone marrow transplantation.

The research ­ conducted by postdoctoral fellows Markus Uhrberg and Nick Valiante in the lab of Peter Parham, professor of structural biology ­ focused on enigmatic white blood cells called natural killer cells.

Natural killer (NK) cells have been largely ignored by immunologists drawn to T and B cells, the big guns of the adaptive immune system. This obscurity is what inspired the Stanford team to learn more about the function of these large granular cells, thought by some to be an archaic remnant of the primitive mammalian immune system. "The NK cell has always been the ugly stepchild," said Valiante. "It was such a black box you knew there had to be something more there."

NK cells spontaneously kill abnormal cells in their vicinity. They recognize and attack tumor cells or those infected by viruses, while sparing cells that are healthy. But how they distinguish between healthy and sick cells has been a mystery.

In the newly published papers, Parham's group presents the first systematic, experimental evidence validating a leading explanation for this phenomenon.

The explanation, known as the missing-self model, was first proposed in 1986. It holds that a person's NK cells somehow "know" when a nearby cell lacks some essential component that characterizes the rest of the cells in that person's body. Early support for the model came in the late 1980s when scientists discovered that NK cells have surface receptors that recognize target molecules on neighboring cells. These target molecules were the so-called transplantation antigens ­ the human leukocyte antigens (HLA) that exist on the surface of almost all cells of the body and that differentiate an individual's cells from those of almost everyone else.

Immunologists theorized that when an NK cell encounters "self" HLA antigens, it recognizes the target cell as friend, not foe, and leaves the cell in peace; but if it fails to detect these antigens, it views the cell as diseased or an invader, and kills it. This system for recognizing "self" or "missing self" offered a compelling explanation of how NK cells distinguish healthy cells from sick ones, because many tumor cells and virally infected cells turn off their production of HLA antigens to escape detection by other cells of the immune system.

Until now, however, no one had methodically tested these predictions and provided definitive evidence that the model actually works. "The theory was there, but no one had tested it at the level of the organism," said Valiante. "Others had tried, but they were looking only at a single [NK cell-HLA] interaction in many different individuals. Our approach was to look at only a few individuals but to look at all possible interactions that could occur."

Valiante and Uhrberg analyzed more than 100 single NK cells from each of two unrelated people who provided blood for the study and whose "self" HLA antigens were known. Valiante painstakingly isolated and cultured individual NK cell clones and documented their killing response to various "self" antigens. Uhrberg devised a DNA-typing method to define which receptors were expressed on each NK cell.

With the new typing system, the researchers were able to correlate receptor expression with the cell's ability to recognize "self" antigens. The results showed that every NK cell could be inhibited by one or more "self" HLA antigens. A set of up to 11 different receptors could be displayed on the NK cell surface in many different combinations. With such an array of receptors to choose from, each cell was assured of being able to recognize the relevant "self" HLA antigens and restrain its natural homicidal urges. If the "self" component was missing, the abnormal cell was killed.

The immediate implication of this work, said Uhrberg, is that NK cells play an important role in the delicate area of bone marrow transplantation.

Clinicians are always careful to match transplant recipients with donors who have the same HLA antigens. It is well accepted that introduction of a foreign HLA molecule from the donor will result in rejection of the grafted tissue. However, even when there seems to be a good match, the grafted tissue is sometimes rejected for no apparent reason. The new research points to the patient's NK cells as a culprit in such rejections.

If the recipient's NK cells detect the absence of a "self" HLA antigen during surveillance of the transplanted tissue, they will begin killing the donor cells. Therefore, in order to improve outcomes, donors and recipients need to be matched not only for their HLA type but also for their NK cell receptors.

Prospective matching for these receptors has never been attempted, but the new research suggests that complementary HLA antigens and NK cell receptors may be important for better transplant success ­ and Uhrberg's typing method provides the tool to achieve it.

"If we can extrapolate from these two [human] subjects, and I think we can, by knowing the [NK cell receptor and HLA] types of donors and recipients we can make pretty accurate predictions about possible bad effects," Valiante said.

"Physicians are constantly asking which factors improve transplantation outcome," Uhrberg said. "The new data will encourage people to look for these differences in NK cell receptors because they could have an influence on transplantation outcome."

Uhrberg and Valiante attribute much of the project's success to a melding of complementary research skills: Valiante's long history in cellular immunology, Uhrberg's strength in molecular immunology, and Parham's wealth of experience in HLA structure and function. A productive collaboration with Drs. Lewis Lanier and Joseph Philips of DNAX Research Institute of Molecular and Cellular Biology, in Palo Alto, provided the final necessary ingredient. Funding for the project was provided by grants from the National Institutes of Health and the Leukemia Society of America.

Timing was also crucial, the researchers agree. "It was the right time to ask one of the big questions [about NK cells]," said Valiante. "Three years ago it was not possible to do these studies. The receptors hadn't been characterized yet; there were no molecular data."

Now they are both excited about the publication of their results in Immunity.

Look for the NK cell on the cover. SR