Discovery of immune tolerance switch could yield better IBD treatments

Weill Cornell Medicine investigators made an unexpected finding about how the immune system normally suppresses inappropriate chronic inflammation in the intestine, potentially opening new avenues for therapies against inflammatory bowel disease (IBD), food allergy and other autoimmune conditions.

The study, published April 24 in the Journal of Experimental Medicine, focused on the cell-to-cell signals required for the immune system to tolerate commensal gut microbes as well as foreign proteins from food. The researchers examined a signal that had been considered necessary for expanding the population of tolerance-enforcing immune cells. They found unexpectedly that only blocking this signal was effective for driving tolerance in intestine through a specific cell subset - and powerfully suppressed gut inflammation in a preclinical model.

"We think this is a paradigm-shifting discovery that will lead to new treatment approaches for chronic inflammatory disorders of the intestine," said study senior author Gregory Sonnenberg, the Henry R. Erle, M.D.-Roberts Family Professor of Medicine and associate vice chair of research in medicine, and faculty member of the Division of Gastroenterology & Hepatology and the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.

The study's lead and co-corresponding author is Mengze Lyu, an instructor of microbiology and immunology in Medicine and member of the Sonnenberg Laboratory.

How the immune system distinguishes friend from foe in different organs and tissues is a puzzle that has never been fully solved, and disorders of inappropriate immune activation remain common - particularly in the gastrointestinal tract, where foreign molecules from food and gut-resident microbes abound. Forms of IBD, particularly Crohn's disease and ulcerative colitis, and other gut inflammation conditions affect millions of people in the United States.

The gut relies heavily on local immune cells with distinct properties, complicating efforts to understand gut immunology. For example, prior research has shown that immune tolerance in the gut is enforced largely by a distinct subset of regulatory T cells called Treg cells that express the transcription factor RORgt. The Sonnenberg lab has been at the forefront of this area of research, where they were the first to discover novel antigen-presenting cells (APCs) expressing RORgt that are enriched in the gut and necessary for immune tolerance. Drs. Lyu and Sonnenberg and their colleagues also have found that gut RORgt+ Treg cells are dependent upon direct signals from these RORgt+ APCs.

Despite these gut-specific distinctions, the requirement for APCs in Treg cell or other T-cell activation is a general one - part of a "two-factor authentication" system that helps regulate immune cell activity. What immunologists call Signal One in this system is the APC's presentation, to a T cell, of the target molecule fragment, or "antigen."

In the new study, the researchers examined Signal Two, which for Treg cells and other T cells outside the gut involves the binding of a different set of receptors on T cells and APCs.

To the scientists' surprise, the usual "Signal Two" coupling of Treg cells and APC receptors, in the presence of Signal One, did not trigger an expansion of gut RORgt+ Treg cells. What did work, in combination with Signal One, was blocking that Signal Two coupling, which expanded the gut RORgt+ Treg cells and prevented gut inflammation in a preclinical model. Importantly, this is the exact opposite of what happens with conventional Treg cells outside of the gut, further highlighting the unique and complicated features of the intestinal immune system.

There is already an approved drug called CTLA4-Ig or Abatacept that blocks the Signal Two interaction. Although it failed to benefit patients with IBD in a 2012 clinical report, the experiments by Lyu and Sonnenberg and their colleagues found that the RORgt+ APCs required for gut immune tolerance are depleted in inflammatory bowel disease - depriving gut RORgt+ Treg cells of the critical Signal One that is needed to trigger their expansion in combination with Signal Two blockade.

"Our results suggest that CTLA4-Ig could be effective against inflammatory bowel disease, if we could restore RORgt+ APCs that are missing, or give CTLA4-Ig to patients who are in remission and still have these cells present and functional in the intestine," Lyu said.

The researchers now are investigating these possibilities. And since gut RORgt+ Treg cells are protective in food allergy, adverse events from cancer immunotherapies, and other chronic inflammatory diseases, they suspect that the same Signal Two-blocking strategy could be broadly harnessed to promote gastrointestinal health.

This work was supported by grants from the National Institutes of Health; an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund; the Meyer Cancer Center Collaborative Research Initiative; the Cancer Research Institute; and Linda and Glenn Greenberg.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.