Thousands of bacterial and other microbial species live in the human gut, supporting healthy digestion, immunity, metabolism and other functions. Precisely how these microbes are protected from immune attack has been unclear, but now a study led by Weill Cornell Medicine investigators has found that this immune "tolerance" to gut microbes depends on an ancient bacterial-sensing protein called STING—normally considered a trigger for inflammation. The surprising result could lead to new treatments for inflammatory bowel disease and other conditions involving gut inflammation.
In their study, reported June 16 in Immunity, the investigators focused on group 3 innate lymphoid cells (ILC3s), immune cells that dwell in the mucosal lining of the gut. Their previous research revealed ILC3s' essential role in preventing immune attacks on gut bacteria. In the new study, they showed that this crucial function in ILC3s depends on STING—such that moderate STING signaling induces immune tolerance, whereas higher levels of STING signaling cause the deaths of ILC3s and the loss of tolerance.
"STING turns out to have a unique and unexpected role in these intestinal-resident immune cells, and we think it could be a target for future therapies for gut inflammation," said study senior author Dr. Gregory Sonnenberg, the Henry R. Erle, M.D.-Roberts Family Professor of Medicine, head of basic research in the Division of Gastroenterology and Hepatology and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.
Innate lymphoid cells often function as "first responders" in mucosal surfaces such as the airway and gut. Dr. Sonnenberg's laboratory discovered RORgt+ antigen-presenting cells, which include a subset of ILC3s, and in 2022, they also discovered that this distinct subset of ILC3s can induce immune tolerance to specific gut microbes by presenting pieces of the microbes to immune-damping T cells called Treg cells. In the new study, the researchers sought to identify how these ILC3s detect gut bacteria in the first place.
Although immune cells in general are known to detect bacteria using a variety of bacteria-specific sensor proteins, the team found that, in mice, tolerance-inducing gut ILC3s sense bacteria through STING. In evolutionary terms, STING is one of the most ancient microbial sensors known to biology, and is found in most animals. STING signaling can be activated directly and indirectly by triggers, including molecules produced by bacteria.
Although STING signaling in most immune cells is pro-inflammatory, the researchers discovered that bacteria-related STING signaling in these gut ILC3s causes the immune cells to migrate to nearby lymph nodes for their anti-inflammatory, tolerance-inducing encounters with Treg cells. They also observed that when the STING sensor is deleted from the ILC3s, mice become much more susceptible to inflammation caused by gut bacteria.
To their surprise, the scientists found that a high level of STING signaling, driven by a generally inflammatory gut environment, also reverses immune tolerance—by killing the ILC3s. In collaboration with the Roberts Institute for Research in IBD Live Cell Bank, the researchers
found evidence of this overactive STING signaling, and ILC3 depletion, in gut tissue from patients with inflammatory bowel disease.
"The key functions of STING in the gut have been controversial—some studies have found that it is protective against inflammation, while others have found that it is pro-inflammatory," said study first and co-corresponding author Dr. Wenqing Zhou, an instructor of microbiology and immunology in medicine in the Sonnenberg lab. "Our findings suggest a solution to this puzzle."
The study thus helps scientists understand how mammals have adapted to their gut-dwelling bacterial guests. To Drs. Sonnenberg and Zhou, the results also suggest that modulating STING signaling to bring it into a tolerance-inducing range, and even replacing lost ILC3s, could be powerful therapeutic strategies against gut inflammation.
