Key Bacterial Sensor Triggers Immune Tolerance to Gut Microbiota

Recent research led by investigators at Weill Cornell Medicine has unveiled a critical mechanism by which the human immune system establishes tolerance to gut microbes, a vital aspect of maintaining gut health. This discovery centers around an ancient protein known as STING, which has traditionally been associated with triggering inflammation.

Within the intestinal mucosa, a specialized group of immune cells, known as group 3 innate lymphoid cells (ILC3s), play a pivotal role in preventing harmful immune responses against beneficial gut bacteria. The research team demonstrated that the immune tolerance afforded by these ILC3s is heavily reliant on STING signaling. They found that moderate activation of STING promotes immune tolerance, while excessive STING activity leads to the depletion of ILC3s and a breakdown of tolerance.

According to Dr. Gregory Sonnenberg, a prominent figure in this study, the unexpected role of STING within ILC3s presents new avenues for therapeutic interventions targeting gut inflammation. ILC3s are often the first line of defense in mucosal areas, including the gastrointestinal tract, and their ability to foster tolerance to gut microbiota is crucial.

Previous research identified specific antigen-presenting cells within the ILC3 population that can encourage immune tolerance by interacting with Treg cells, which are responsible for dampening immune responses. The current study aimed to unravel the mechanisms through which these ILC3s initially recognize gut bacteria.

While it is established that immune cells utilize various sensor proteins to detect bacteria, this study revealed that ILC3s specifically rely on STING for this purpose. STING is one of the most ancient microbial sensors found across many animal species and can be activated by various bacterial-derived molecules.

Interestingly, while STING typically promotes inflammation in most immune contexts, the findings indicate that in ILC3s, STING signaling directs these cells to migrate to nearby lymph nodes, facilitating interactions that foster tolerance with Treg cells. Conversely, the deletion of STING in ILC3s resulted in heightened susceptibility to inflammation from gut bacteria in mouse models.

Alarmingly, the researchers discovered that heightened STING activity, often triggered by inflammatory environments within the gut, can reverse immune tolerance by leading to the death of ILC3s. Through collaboration with the Roberts Institute for Research in IBD Live Cell Bank, evidence supporting overactive STING signaling and ILC3 depletion was identified in the gut tissues of patients suffering from inflammatory bowel disease.

The dual role of STING has been contentious, with some studies suggesting it offers protection against inflammation, while others indicate its inflammatory potential. This research provides clarity regarding STING's functions within the gut environment.

Understanding how mammals manage their symbiotic relationships with gut bacteria is crucial for advancing treatment strategies for inflammatory conditions. The researchers propose that adjusting STING signaling towards a tolerance-promoting threshold, alongside potential restoration of ILC3 populations, could be effective strategies in addressing gut inflammation.