Immunology, Medicine and Translational Research
University of California, San Francisco
Dr. Locksley is also Sandler Distinguished Professor of Medicine and director of the Sandler Asthma Basic Research Center at the University of California, San Francisco.
Tracking the Foundations of Allergic Immunity
As chief resident at the University of California, San Francisco, Medical Center in 1979, Richard Locksley spent a couple of hours each Friday with his department chair, Lloyd Hollingsworth "Holly" Smith. Propping his feet on the desk, Smith would discuss the week's most interesting patients. But he always wandered off into basic science. "We would be in the middle of talking about a patient with, say, renal failure, and he would go off on how ions are transported. He made science so compelling that it was impossible not to think, 'This is too interesting not to do,'" Locksley recalls.
So he decided to specialize in infectious diseases. "I was intrigued by the idea of two genomes [of the pathogen and host] competing for the same space," he explains.
As a postdoc at the University of Washington, Locksley worked with Seymour Klebanoff, who studied immune cells called neutrophils, and Christopher Wilson, who made some of the early observations on interferon gamma. He began by studying Toxoplasma, a tropical intracellular parasite. But while reading about another parasite, he came across an intriguing observation. "I just couldn't let it go," he says, "though Seymour looked at me as if I had lost my mind when I said I wanted to pursue the immunology of Leishmania." This tropical protozoan infects more than 12 million people, causing chronic ulceration of the skin and internal organs.
The observation that intrigued Locksley involved immune cells called T helper cells. One strain of mice infected with Leishmania recovered spontaneously, and its T helper cells protected a related strain. But when that strain was infected, it died, and its T helper cells sickened the first strain. "It was intriguing to me that the same cell type could mediate these completely different disease outcomes," Locksley says.
He showed that T helper cells of the susceptible and resistant strains secrete different cytokines (molecules that communicate with other cells) in response to Leishmania. Those from the resistant mice secrete interferon gamma, which marshals other cells to kill intracellular pathogens. The susceptible mice make T helper cells that secrete interleukin 4 (IL-4), which helps wounds heal but doesn't command killing. "That was the first demonstration that T helper subsets exist in vivo and mediate these different outcomes of disease within this Leishmania model," Locksley says.
T cells are part of the adaptive immune system, which responds to pathogens with astounding specificity and confers immunity to the host. But there is also an innate immune system, which paints with broader strokes, providing a general but more immediate response. "So although T cells occupied my interest when I first started research, we came to realize that a far more ancient program, the innate immune system, recognizes and responds to pathogens first," Locksley says.
When the innate immune system misfires, it contributes to allergies. After exposing mice to various allergens, one of Locksley's graduate students noticed that chitinase levels rose sharply in affected tissues, which were infiltrated with eosinophils and basophils. This enzyme breaks down chitin, a polymer that forms the external skeleton of invertebrates such as shrimp and dust mites. "Then the light went on. We realized that all of the allergens we used had chitin in them," Locksley says. "That's the exciting part about science. These observations come up, and they demand an explanation."
His group then showed that chitin prompts immune cells that secrete IL-4 and IL-13 to infiltrate airway tissue. "Could it be that we make chitinase to remove the stimulus for inflammation?" Locksley says. "Is that how we get rid of this insoluble component of insects, molds, or items you happen to inhale or eat?"
Because asthma is so prevalent in children, Locksley is participating in epidemiologic studies of inner-city kids. He is intrigued by the "hygiene hypothesis," which posits an inverse relationship between cleanliness in a child's home and risk of asthma. So his group is determining whether samples containing fewer microbes have more chitin. They are also exploring the normal roles of IL-4– and IL-13–secreting cells. "Those cells didn't grow up to torture us with allergies," he points out.
Locksley says research is so satisfying that it is easy to put the rest of life aside. But since the birth of his twin girls 13 years ago, he has resisted that temptation. An athlete in college, he now coaches the girls' soccer team on Tuesdays and softball team on Thursdays. In 2007, he was voted Coach of the Year by the San Francisco Little League. He says, "Finding the right balance between work and family is an important part of being successful in your scientific endeavors."