Researchers at Weill Cornell Medicine have discovered a novel connection between two key pathways of the mammalian immune system. This finding challenges our understanding of chronic inflammatory bowel diseases (IBD), which affect more than 200,000 people in France. This advancement could pave the way for new targeted therapies, preserving intestinal function and balancing the immune response.
The study, published on June 12 in
Nature, reveals that interleukin-23 (IL-23), an immune factor, acts on type 3 innate lymphoid cells (ILC3). These cells play a frontline role in mucosal tissues like the intestines and lungs. In response to IL-23, ILC3s increase the activity of CTLA-4, a key regulator preventing the immune system from attacking the body and beneficial microbiota. This mechanism shows how IL-23, although pro-inflammatory, helps maintain intestinal health, a function often impaired in IBD.
Gregory Sonnenberg, the lead author and professor at the Jill Roberts Institute for Research in Inflammatory Bowel Disease, emphasizes the importance of this discovery: "This unexpected connection between two major immune pathways controlling health, immunity, and inflammation could allow us to develop more selective therapies."
Postdoctoral researcher Anees Ahmed, the study's lead author, used single-cell RNA sequencing to analyze the effects of IL-23 on various immune cells from a healthy intestine. The results showed that IL-23 strongly activates the CTLA-4 pathway in ILC3. Blocking this pathway leads to severe intestinal inflammation.
To confirm their findings in humans, the researchers used samples from the Jill Roberts Institute Live Cell Bank, which includes patients with IBD and healthy individuals. "This unique resource allowed us to quickly confirm that our findings in mice also apply to human IBD patients," said Gregory Sonnenberg. The validity of the observations was verified in collaboration with Robbyn Sockolow, pediatric gastroenterologist and professor of clinical pediatrics at Weill Cornell Medicine.
The results show that this new immunological pathway is present in the healthy human intestine but becomes defective in IBD patients. "This could explain why IL-23 becomes a driver of intestinal inflammation in human IBD," said Robbyn Sockolow.
The study also suggests that this pathway could be exploited to combat cancer and explain why some patients undergoing immunotherapy suffer from intestinal inflammation. Drugs blocking CTLA-4, used to release the immune system's brakes, can cause severe intestinal inflammation.
Anees Ahmed indicates that further research is necessary before applying these findings to new treatments. He envisions the possibility of developing targeted treatments that avoid ILC3 in the intestine or simultaneously block IL-23. "We could find ways to selectively block CTLA-4 or IL-23 in certain immune cells, which could revolutionize the fight against cancer while protecting the intestine from inflammation," he added.
These discoveries could also have long-term applications for developing new treatments against various IL-23-mediated autoimmune diseases. Drugs targeting IL-23 already exist, but future therapies could control the underlying mechanisms of chronic inflammatory diseases without completely blocking IL-23.
Article author: Cédric DEPOND