The body’s immune response is a balancing act, according to researchers at the University of Pennsylvania School of Dental Medicine, as too much can lead to inflammatory or autoimmune disease, and too little could lead to serious infection. Regulatory T cells, or Tregs, act as brakes on the immune response so it doesn’t go too far.
Controlling Treg numbers and activity is crucial in maintaining health, the researchers said. Targeting the DEL-1 molecule, which promotes the generation and immunosuppressive activity of Tregs, could be an effective way to treat conditions where taming an inflammatory or autoimmune response is desired.
“In earlier work, we saw a correlation. During resolution of inflammation, Tregs numbers went up, and DEL-1 levels went up,” said George Hajishengallis, DDS, PhD, Thomas W. Evans Centennial Professor in the Department of Basic & Translational Sciences. “We wanted to understand how the two were connected.”
Earlier, the researchers used a mouse model of periodontitis to show that DEL-1 promotes the resolution of inflammation, or how it helps the body return to a normal state. In the new study, they relied on this model again to probe the relationship between DEL-1 and Tregs, which, like DEL-1, also become abundant during the inflammation-resolution process.
Mice bred to lack DEL-1 had significantly lower levels of Tregs than mice with DEL-1, but their levels of Th17 cells, a T cell type associated with inflammation, went up. An injection of DEL-1 could restore levels of Tregs in the mice otherwise deficient in the protein. The correlation offered a clue but not evidence of a direct relationship between DEL-1 and Tregs.
“There’s a reciprocity between Tregs and Th17 cells,” said Hajishengallis. “So with this result, we didn’t know if DEL-1 is acting on Tregs or Th17 cells.”
To firm up this connection, the researchers experimented on mouse cells in culture to see if DEL-1 could influence the development of T cells into either mature Th17 or Treg cells. While DEL-1 did not appear to directly influence the generation of Th17 cells, its effect on Tregs “was striking,” Hajishengallis said.
Their findings held when looking in human cells, with the generation of Tregs enhanced in the presence of DEL-1. Also, the researchers found that T cells’ immunosuppressive function, a characteristic supported by Tregs, was strengthened when DEL-1 was present.
With more confidence that DEL-1 was supporting Treg activity, the researchers then uncovered more details about the signaling pathway in which DEL-1 was acting. They found that DEL-1 interacted with a molecule on the T cell surface that induced a transcription factor called RUNX1 that promotes the expression and stability of FOXP3, a master regulator of Tregs.
“Without FOXP3, you cannot have Tregs,” said Hajishengallis.
The researchers also found that DEL-1 was acting epigenetically to stabilize FOXP3 by removing small molecular tags known as methyl groups located in the region of this gene.
FOXP3 deficiencies are linked to serious conditions in human beings. IPEX syndrome, for example, an X-linked condition caused by a FOXP3 mutation, causes people to have very low numbers of Tregs and frequently to develop multiple autoimmune diseases.
Though the researchers had begun with a gum disease model, the believed the link between DEL-1 and Tregs was more universal. So, they investigated a mouse model of acute lung inflammation, finding the same pattern. A dearth of DEL-1 was associated with severely reduced numbers of Tregs and a poorer resolution of inflammation.
The researchers next hope to go deeper into the mechanism, testing whether the source of DEL-1 matters in terms of its regulation of Tregs. Other groups, they note, may want to begin to take the findings in a translational direction to apply them in models of autoimmune diseases, which could be tamed by a shift in balance toward immunosuppression.
“I believe DEL-1 is not just for periodontitis and inflammation, but is also a potential target in autoimmune diseases,” Hajishengallis said.
The study, “The DEL-1/β3 Integrin Axis Promotes Regulatory T Cell Responses During Inflammation Resolution,” was published by The Journal of Clinical Investigation.
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