Cell Biology, Immunology
Dr. Cresswell is also a professor of immunobiology and cell biology at Yale University School of Medicine.
Mechanisms of Antigen Processing
Peter Cresswell's path to immunology research had some twists and turns. He began first and foremost as a chemist: he was one of those kids who blows up things and sets things on fire. "I've had many discussions with other scientists and that behavior is a common phenomenon," he says.
As a 14-year-old, he tried to adapt a procedure for making hydrochloric acid to make hydrobromic acid with supplies from a lab technician friend. "I found that while hydrogen chloride dissolves in water to give hydrochloric acid, hydrogen bromide spontaneously generates bromine in the air. You get a horrible, brownish, dangerous gas that eventually liquefies," he remembers. "I did this in the house, and I had this beaker of bubbling stuff, and brown fumes flowing across the table."
He survived both the fumes and the potential punishment: His parents were out at the time.
After pursuing his love of chemistry in college, where he earned a bachelor's degree in the subject, Cresswell began work on a master's degree in microbiology. He was isolating, purifying, and determining the structure of lipids found in the cell membranes of bacteria.
"Then I realized that what I was doing ended with characterizing the structure of these lipids, and it had little biological significance," he says. A visit to his lab from immunologist Arnold Sanderson intrigued him. "Immunology seemed like an important field that, at that time, was minimally understood at the molecular level."
Cresswell joined Sanderson's lab for his doctoral work, where he was introduced to the major histocompatibility complex, or MHC. This protein family plays a key role in the immune response as well as in autoimmune diseases.
He went on to a postdoctoral stint in Jack Strominger's lab at Harvard. "When I first went there, I was more interested in studying bacterial cell walls, and that's what most of his lab was studying," Cresswell remembers. "But he wanted me to continue working on the MHC. I said okay, and soon after, the field exploded."
When Cresswell started studying the human MHC, only researchers studying organ transplants had any interest in the field, and they were focused on the identity of the best-known MHC proteins, now called class I human leukocyte antigen (HLA) proteins.
"At the time, all we knew was these proteins caused transplant rejection," Cresswell says. Then, in 1974, scientists discovered that cytotoxic, or killer, T cells must recognize a combination of an MHC protein and a foreign protein to be activated.
"I wanted to find out exactly how that combination was formed," says Cresswell. "And most of my career has been spent doing that."
Cresswell started by studying MHC class I molecules. They are found on the membranes of every cell in the body and present foreign antigens to killer T cells. The T cell then destroys the infected cell.
His lab spent years trying to understand how the foreign antigens connect with class I molecules. Recently, the lab identified all the known molecules involved in the process and how they interact.
Another groundbreaking avenue of research happened by chance. Cresswell had purified some class I molecules and injected them into rabbits to make antibodies. As it turned out, the class I molecules weren't exactly pure. The contaminating proteins—the cause of a large fraction of the antibodies—were MHC class II molecules, a key part of the immune system that no one had discovered yet in humans. "That was a happy accident," Cresswell says.
For T cells to recognize class I and class II molecules, foreign peptides must bind to them. Over the years, Cresswell figured out how this happens. One key component for the class II molecules is an enzyme called GILT. "The foreign proteins have to be unfolded to bind to the class II molecules," explains Cresswell. "To unfold them, you need to break disulfide bonds, and GILT does that."
GILT also can work against the body. Cresswell's lab recently discovered that it is necessary for Listeria monocytogenes—one type of bacteria that causes food poisoning—to infect cells. "We made a knockout mouse that lacks GILT, and these mice don't get infected."
Cresswell's lab also studies viperin, which he discovered in the late 1990s. Though the protein sounds snake-like, it's a human virus inhibitor protein. Cresswell has found that viperin helps the body fight flu, herpes simplex, and cytomegalovirus. Recently, other researchers have found that viperin is active against some cold viruses.
"But it's been a problem figuring out how it works," says Creswell. "It seems to change the composition of the membrane of the infected cell. We've made a knockout mouse, but that hasn't helped us yet. It looked like it was going to be quite straightforward, but it's not."