Lanier’s Pursuit of Immune System’s Natural Killers Leads to New Treatment

Lewis Lanier, PhD, a scientific sleuth of “natural killer” cells,
struck a James Bond pose in photos taken for a poster announcing his talk.

Lanier’s studies of cells of the immune system have caused textbooks to be rewritten and opened new avenues for exploring immunotherapies for a range of diseases.

Lanier, American Cancer Society Research Professor and chair of the Department of Microbiology and Immunology at UCSF, presented the lecture on Feb. 14 to a packed crowd in Cole Hall auditorium on the UCSF Parnassus campus, many of them young graduate students and postdoctoral fellows.

“Do science because it is your passion and because you can’t imagine doing anything else,” Lanier advised the young researchers.

Lanier’s own abiding passion is for research on the immune system.

In 1981, Lanier began studying one of the armed forces of the immune system, called “natural killer” or NK cells.  Working with cell-sorting technology at Becton Dickinson Immunocytometry Systems and monoclonal antibodies made by his first postdoctoral fellow Joseph Philips, Lanier discovered a receptor that marks the cells. They soon discovered that the receptor, called CD16, allowed the cells to kill cells that had been previously targeted by IgG antibodies, leading to their being named natural killer cells.

Some immunologists didn’t believe Lanier had identified an important and unique cell population. It was suggested that NK cells were merely immature lymphocytes – the already renowned T cells of the immune system. A few scientists remained reluctant to acknowledge the evidence for years. Lanier’s discovery was comparable to finding out that the US Marines is an important branch of the armed forces, after the other services had long been recognized.

And in fact some cells of the immune systems and the protective antibodies that some of them make and secrete have been known for more than a century. A basic understanding of antibodies accelerated vaccine development in the mid-1900s.

But NK cells are only now being accorded a full measure of respect. And in an area when treatments based on manipulating the immune system are at last hitting their stride, it’s still early day for therapies based on a new understanding of these natural killers.

Understanding the Role of NK Cells and the Immune System

Lanier moved his laboratory research to the DNAX Research Institute of Molecular and Cellular Biology Inc. in 1991, and he joined the UCSF faculty as a professor in the Department of Microbiology and Immunology and the Cancer Research Institute in 1999. Lanier became chair of the department in 2009 and was elected to the National Academy of Sciences in 2010.

He has continued to make basic discoveries about the roles of NK cells ever since he initially described this unique branch of the immune system. He has identified many additional cell-surface receptors on NK cells that help activate or inhibit immune functions when signaling molecules attach to the receptor.

Lanier’s lab team has found that NK cells, which are fast responders when infection strikes, are even more eager when they encounter a pathogen for a second time. Like T and B lymphocytes, they have “memory,” and can ramp up their numbers quickly upon re-exposure months or years later. This immune-cell memory is the basis for the efficacy of vaccines.

To launch their attack on pathogens, lymphocytes of the immune system normally require infected cells to display bits of pathogen proteins in the arms of MHC class I proteins. But Lanier’s lab team determined that a key NK cell receptor called NKG2D helps natural killers to mount an attack on cancer cells, which learn to avoid displaying MHC class I molecules. NK cells rely on the display of MHC class I molecules to recognize our own cells, and to refrain from attacking them.

Lanier and his postdoctoral fellows have found that NK cells can directly target some proteins made by certain pathogens, often those that play a role in chronic infection.

Over the past few years Lanier has been exploring the role of NK cells in chronic infection and immune tolerance more deeply. It had been thought that NK cells had to learn to tolerate MHC class I “self” molecules in order to mature and function against pathogens. However, Lanier’s lab group recently discovered that the NK cells that keep certain chronic infections in check, such as cytomegalovirus, lack the receptor that is inhibited by MHC class I molecules. In addition, NK cells sometimes contribute to the rejection of allogeneic bone marrow cell transplants, a phenomenon that Lanier is investigating.

At UCSF, Lanier and other laboratory and clinical scientists now are working together to explore the therapeutic potential of natural killer cells in battling deadly brain tumors, hepatitis B and cytomegalovirus.

A scientist’s Eureka moments can more than make up for bad days in the lab, Lanier told young researchers in the audience. During such a moment, the thought running through a scientist’s mind may be, “I just learned something nobody else ever knew, and it might change the textbooks, and it might change the world.”

What’s the key to making scientific discoveries? “Be smart. Work hard. Be lucky,” Lanier said. As a “corollary,” he added, “You have to know when you got lucky.”

Photo by Wilson Hardcastle