Left, a living dendritic cell that has been hyperactivated by oxPAPC. Right, a dead dendritic cell. Image: Jonathan Kagan, Boston Children’s Hospital
Left, a living dendritic cell that has been hyperactivated by oxPAPC. Right, a dead dendritic cell. Image: Jonathan Kagan, Boston Children’s Hospital
Harvard Medical School researchers at Boston Children's Hospital report that a fatty chemical naturally found in damaged tissues can induce an unexpected kind of immune response, causing immune cells to go into a “hyperactive” state that is highly effective at rallying infection-fighting T cells.
The findings, published online in Science, could enhance vaccines and make them much more effective.
The researchers, led by Jonathan Kagan, saw a five times greater adaptive immune response in mice when using the chemical, called oxPAPC. They believe that oxPAPC or a related synthetic compound could be used to help immunize people against a wide range of infections.
“We think this could be a general means to increase response to any type of vaccine,” said Kagan, HMS associate professor of pediatrics at Boston Children’s.
oxPAPC targets only dendritic cells—sentinels that circulate around the body searching for microbes and activating T cells to destroy the invaders. Previously, it was thought that dendritic cells (also known as antigen-presenting cells) have just two states: an inactive state, in which they can search for microbes, and an active state, in which they have encountered a microbe and gain the ability to activate T cells.
“We identified a naturally occurring molecule that creates a heightened, ‘hyperactive’ state of dendritic cell activation,” said Kagan. “These hyperactive cells live for a long time and are the best activators of T cells that we know of, so this could be a very useful tool in vaccine development.”
While the work was in mice, Kagan noted that other studies have shown that the biology of dendritic cells is similar in mice and humans.
In particular, when they gave oxPAPC to mice, they saw strong activation of memory T cells, which respond more effectively to invaders than other kinds of T cells, but their responses are not efficiently elicited by ordinary activated dendritic cells.
Kagan’s team further showed that hyperactivated dendritic cells make a critical protein, IL-1ß, that triggers memory T cell production. Dead dendritic cells also release IL-1ß, but only for a short period of time. Hyperactivated dendritic cells produce IL-1ß for longer periods, which likely explains why they are such effective stimulators of memory T cells.
Finally, the researchers found that oxPAPC’s key target is an enzyme called caspase-11. When activated by other molecules, caspase-11 triggers cell death and inflammation. But when activated by oxPAPC, the enzyme promotes hyperactivation of dendritic cells.
“These discoveries highlight that dendritic cells and caspase-11 can have more than one activation state, which was never before known,” Kagan said.
Kagan and Boston Children’s have filed for a patent on this work.
Supporters of the study include the National Institutes of Health (grants AI093589, AI072955, P30 DK34854, 1R01AI121066-01A1 and HDDC P30 DK034854), Mead Johnson & Company, the Burroughs Wellcome Fund and the Cariplo Foundation.
Adapted from a Boston Children’s news release.
