Can we hypercharge vaccines?
Tapping a chemical we already make could enhance T-cell production
The researchers, led by Jonathan Kagan, PhD, got 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," says Kagan, also an associate professor at Harvard Medical School.
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 commonly 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," says 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."
In particular, when they gave oxPAPC to mice, they saw strong activation of memory T-cells. Memory T-cells respond more effectively to invaders than other kinds of T-cells, but 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 times, 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," says Kagan.
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