A protein produced by gut immune cells orchestrates both immune protection against pathogens and immune tolerance of gut bacteria, according to a study led by Weill Cornell Medicine investigators. The discovery illuminates the complex biology of the gut immune system and could lead to better-targeted treatments for inflammatory bowel disease (IBD).

In the study, published July 7 in Immunity, the researchers sought a better understanding of an immune protein called TL1A. Found at high levels in the gut tissues of patients with IBD, and linked to a variety of inflammatory conditions in genetic studies, TL1A is considered a promising therapeutic target, though its molecular links to inflammatory disease are not well understood. The researchers determined that in gut immune cells TL1A exerts much of its immune-stimulating effect against pathogens through BHLHE40, a protein that is a master-switch for many genes. To their surprise, they found that the protein also has a critical role in maintaining immune tolerance to beneficial microbes that normally live in the gut, helping prevent unnecessary inflammation.

“These findings reveal BHLHE40 as a major coordinator and regulator of the TL1A-specific response and may allow a more selective targeting of this pathway to benefit IBD patients,” said study senior author Dr. Randy Longman, M.D. ’07, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center and a professor of medicine at Weill Cornell Medicine.

The study’s first author was Wei Yang, a postdoctoral research associate in the Longman Lab.

IBD is a set of relapsing-remitting gut inflammation conditions – Crohn’s disease and ulcerative colitis – that collectively affect between 2.4 and 3.1 million Americans. Treatment traditionally has involved broad immune suppression, but advances in immunology in recent decades have led to the development of more narrowly targeted strategies, including TL1A-blocking antibodies now in clinical trials in patients with ulcerative colitis.

In the study, the researchers observed that in gut-resident immune cells called ILC3 cells, one of the most striking effects of TL1A is a powerful increase in the production of BHLHE40. Analyses of existing data on patients with IBD showed that BHLHE40 is also elevated in these cells during human disease. In mice, BHLHE40 in ILC3s was necessary for an effective defense against a pathogenic gut bacterium, but the same pathway could also fuel IBD-like gut inflammation – mice without the gene had milder disease signs. These findings suggest that BHLHE40 is key to balancing beneficial and harmful effects of the immune response in the gut.

In addition to regulating effects in ILC3 cells, BHLHE40 had a very different function in an ROR-gamma-t antigen-presenting cell, another population of immune cells. These cells enforce immune tolerance to beneficial gut microbes by activating regulatory T cells (Tregs), which dampen immune activity in the vicinity of those microbes. The scientists found that BHLHE40 was needed to induce proper Treg activation – its absence in mouse models of colitis led to more severe inflammation.

Surprisingly, the researchers discovered that BHLHE40 also helps promote immune tolerance from within ILC3s themselves. There, the experiments showed, the regulatory protein induces the expression of a cell-surface protein, OX40L, which provides a key signal to microbe-protecting Tregs – without BHLHE40, OX40L and Treg levels were much lower. Together, the findings reveal that BHLHE40 coordinates communication among three key immune cell types to promote tolerance in the intestine.

“This gives us a new model or paradigm for how immune cells in mucosal surfaces like the gut work together to maintain barrier tolerance and host defense,” Yang said.

The findings may have clinical implications, because they open up the possibility of targeting specific factors downstream of TL1A signaling to reduce inflammatory immune activity in the gut without compromising tolerance to beneficial gut microbes. Moreover, markers of these factors, such as OX40L, might be useful for tracking patients’ responses to therapies, Longman said.

“We’re looking now at translational opportunities in this BHLHE40 pathway, and more generally are working to broaden our understanding of this protein’s role in gut immunity,” he said.

The research reported in this story was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Randy Longman.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.