Washington University in St. Louis
Dr. Yokoyama is also a professor of medicine and of pathology and immunology at Washington University School of Medicine in St. Louis, where he is the Sam J. and Audrey Loew Levin Professor of Arthritis Research and director of the Medical Scientist Training Program.
Tissue-Resident Natural Killer Cells
When Wayne Yokoyama was elected to the National Academy of Sciences in 2007, he contacted his scientific mentors, including his high school biology teacher. Yokoyama is still in touch with his high school biology teacher because he is grateful to the man who started him on the path to become a physician-scientist.
Growing up in Hawaii during the 1960s space race, Yokoyama had been intrigued by astronomy. But it was his high school teacher Miles Muraoka who introduced him to biology with a laboratory-oriented class.
Muraoka also supported him through his father's death, keeping him engaged with science. In 1969, he helped Yokoyama obtain a summer research fellowship at a Hawaii hospital with Mitsuo Yokoyama (no relation) to do what was then crude "tissue typing." At the time, why certain donor and recipient tissues might be incompatible was unknown, and Yokoyama's lab results were confusing.
Not dissuaded by research's complexity, Yokoyama decided that summer to become a biomedical investigator. His lab work and a news event made him appreciate science's relevance to society. That summer, Hawaii's first kidney transplant had been performed. When Yokoyama saw the surgeon on television, the physician explained he had to do the procedure in identical twins. Young Yokoyama immediately realized why: the twins had matching tissues, so the recipient would not reject his twin's donor tissue, unlike the incompatibility he saw in the lab with unrelated people. How research might improve medical care impressed the 17-year-old.
His project ultimately won Hawaii's highest high school science fair prize, allowing Yokoyama to win a scholarship to the University of Rochester to study biology. He obtained an M.D. at the University of Hawaii and did 11 years of clinical and research training before becoming an independent researcher. Yokoyama came to Washington University School of Medicine, St. Louis, in 1995.
During his career, Yokoyama has remained interested in immunology and trained with physician-scientists Parker Staples (University of Rochester), Eugene Lance (University of Hawaii), Robert Ashman (University of Iowa), David Cohen (NIH), and Ethan Shevach (NIH). He made fundamental discoveries about how certain immune system cells, called natural killer cells, in the "innate" immune system, protect us from infection and cancer. Innate immunity allows quick control (hours to days) of infected cells and tumors. T cells and B cells, the "adaptive" arm of the immune system, finally eliminate invaders and cancer cells, but take much longer (days to weeks) to mount a response.
Before Yokoyama's findings, many scientists had dismissed natural killer cells as insignificant to immunity because they, unlike T and B cells, didn't seem to be discriminating against particular pathogens or tumors.
But Yokoyama's findings revealed that natural killer cells have receptors for cell surface molecules on infected and tumor cells that determine if the natural killer cells will selectively destroy unhealthy cells.
In 1992, Yokoyama identified the first target cell–specific receptor on a natural killer cell, the Ly49A receptor, which stops it from annihilating a healthy cell. Yokoyama found these inhibitory receptors seek a target molecule called MHC class I that is normally expressed on other cells, and this allows natural killer cells to ignore them. If MHC class I is gone, as happens in unhealthy or infected cells, natural killer cells may obliterate those cells. By 1995, other scientists identified inhibitory receptors on human natural killer cells.
But the inhibitory receptors did not fully explain how natural killer cells demolish cells. In 2001, Yokoyama found another receptor, called Ly49H, which can activate natural killer cells to kill because it recognizes a viral protein on the surface of infected cells.
Further research in 2005 by Yokoyama revealed that natural killer cells need to acquire the ability to function. If natural killer cells are not "licensed," as Yokoyama calls the process, natural killer cells later in life cannot work. During licensing, an immature cell's inhibitory receptor, such as Ly49A, has a second role when it binds MHC class I because it then allows the cell to change and become functionally competent.
In giving rise to functionally competent cells, the inhibitory receptors and MHC molecules thus dictate how potent the natural killer cells might be in any individual, Yokoyama explained. People with more robust natural killer cells might be better able to fight off pathogens and tumors. Although scientists have studied the relationship among MHC variants and certain diseases in terms of T cell activity, Yokoyama's research suggests that variability in the natural killer cell potency, due to their inhibitory receptors and MHC molecules, may also be involved in disease susceptibility.
These days, Yokoyama, a rheumatologist, sees patients, and his lab is working out how natural killer cells work and fight infections. As he looks back on his career, Yokoyama is thankful he was able to pursue his youthful ambition and hopes his future contributions continue to improve understanding of the human condition. And like his biology teacher, he hopes to inspire young students to pursue careers in scientific investigation.