Immune response is a balancing act: Too much can result in inflammatory or autoimmune disease; too little could lead to a serious infection. Regulatory T cells, or Tregs, are important players in striking this balance, acting as “brakes” on the immune response so it doesn’t go overboard.
Because of this, controlling the numbers and activity of Tregs is the most important in maintaining health. New findings from a multi-institutional team, including the School of Dental Medicine’s George Hajishengallis, propose that targeting the molecule DEL-1, which promotes the generation and immunosuppressive activity of Tregs, could be a good way to treat conditions where taming an inflammatory or autoimmune response is desired.
The team reported their findings in the Publication of Clinical Investigation.
“In earlier work, we saw a correlation: All through resolution of inflammation, Tregs numbers went up and DEL-1 levels went up,” Hajishengallis says. “We wanted to know the way the two were connected.”
Hajishengallis and colleagues, including Triantafyllos Chavakis of Technical University Dresden, had earlier used a mouse mannequin of periodontitis, severe gum disease, to show that DEL-1 promotes the resolution of inflammation–in other words, helps the body return to a normal state. In the new study, they relied on this mannequin again to probe the relationship between DEL-1 and Tregs which, like DEL-1, also develop into abundant all the way through the inflammation-resolution process.
Mice that were bred to lack DEL-1 had significantly lower levels of Tregs than mice with DEL-1. Meantime their levels of Th17 cells, a T cell kind associated with inflammation, went up. An injection of DEL-1 could restore levels of Tregs in the mice in a different way deficient in the protein.
The correlation offered a clue but no evidence of an instantaneous relationship between DEL-1 and Tregs. “There’s a reciprocity between Tregs and Th17 cells,” says Hajishengallis. “So with this result, we didn’t realize whether DEL-1 is acting on Tregs or Th17 cells.”
To firm up this connection, they performed experiments the use of 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 “used to be striking,” Hajishnegallis says. Their findings held when taking a look in human cells, with the generation of Tregs enhanced in the presence of DEL-1.
What’s more, the researchers found that T cells’ immunosuppressive function–a characteristic supported by Tregs–was strengthened when DEL-1 used to be present.
With more confidence that DEL-1 used to be supporting the activity of Tregs, the researchers pursued a series of extra experiments that unveiled more details approximately the signalling pathway in which DEL-1 used to be acting. They found that DEL-1 interacted with a molecule on the T cell surface which induced a transcription factor called RUNX1 that promotes the expression and stability of FOXP3, a “master regulator” of Tregs. “Without FOXP3 you can’t have Tregs,” Hajishengallis says.
Their work showed that DEL-1 used to be also acting epigenetically to stabilize FOXP3 by removing small molecular “tags” referred to as methyl groups located in the region of this gene.
FOXP3 deficiencies are indeed linked to serious conditions in humans. IPEX syndrome, as an example, an X-linked condition caused by a FOXP3 mutation, causes people to have very low numbers of Tregs and, continuously to develop more than one autoimmune diseases.
Though the researchers had begun with a gum disease mannequin, they believed that the link between DEL-1 and Tregs used to be more universal and thus investigated the link in a mouse mannequin of acute lung inflammation, finding the same sample: A dearth of DEL-1 used to be associated with severely reduced numbers of Tregs and a poorer resolution of inflammation.
In future work, Hajishengallis and his collaborators hope to go deeper into the mechanism, testing if the source of DEL-1 affairs in relation to its regulation of Tregs. Other groups, they note, may wish 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 the balance toward immunosuppression.
“I imagine DEL-1 is not only for periodontitis and inflammation but may be a potential target in autoimmune diseases,” Hajishengallis says.
(This story has been published from a wire agency feed without modifications to the text.)
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