Bridging our innate and adaptive immune systems, dendritic cells are sentinels that circulate in the body searching out microbes and activating T-cells to destroy the invaders. They do this by presenting bits of the microbes on their surface—explaining why they’re often called antigen-presenting cells.
Reporting in Science this week, researchers describe a way to push dendritic cells into a “hyperactive” state, supercharging their ability to rally T-cells.
The key player, a fatty chemical called oxPAPC, is naturally found in damaged tissues and atherosclerotic plaques. It selectively targets dendritic cells and could, the researchers believe, enhance people’s immunity to a wide range of infections.
“We think this could be a general means to increase response to any type of vaccine,” says lead researcher Jonathan Kagan, PhD, of Boston Children’s Hospital. “These hyperactive dendritic cells live for a long time and are the best activators of T-cells that we know of.”
When they gave oxPAPC to mice, Kagan, first author Ivan Zanoni, PhD, and colleagues enhanced their adaptive immune response five-fold. In particular, 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 normal 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 memory T-cell stimulators.
Dual activation states
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, who is part of the department of Gastroenterology at Boston Children’s Hospital and an associate professor at Harvard Medical School.
Kagan is further exploring how oxPAPC hypercharges dendritic cells via caspase-11. While the work was done in mice, he notes that other studies have shown that the biology of dendritic cells is similar in mice and humans, so he’s optimistic about oxPAPC as a tool for vaccine development and is hopeful that it will be effective when given nasally or orally.
Kagan and Boston Children’s Technology and Innovation Development Office (TIDO), have filed for a patent on this work and are seeking investor interest so they can move oxPAPC or a similar compound toward a clinical trial. For inquiries, contact Abbie.Meyers@childrens.harvard.edu.
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.