A microscopy image showing intestinal barrier cells (outlined in yellow with blue DNA), ILC2 cells (pink) and mucus-producing cells (turquoise).

26 May 2026

By Betty Zou

University of Toronto researchers have shown, for the first time, that organ-specific cues prompt some immune cells to become uniquely adapted to the tissues in which they reside.

These findings, published recently in Science Immunology, provide new insights into how the same cells behave and function differently depending on their local environment and open the door to the possibility of targeted, tissue-specific treatments for immune-related conditions.

The study focused on a type of immune cells called group 2 innate lymphoid cells (ILC2s), which are found in different tissues including the intestine, lung and skin. These cells play a key role in allergies, asthma and the immune responses against respiratory viruses and parasites.

Study senior author Arthur Mortha says that innate lymphoid cells (ILCs) have long been overlooked in immunology research because researchers have not traditionally focused on the organs where these cells are found.

“They are particularly important because they’re the architects of the immune response that happens within specific organs,” says Mortha, who is an associate professor of immunology at U of T’s Temerty Faculty of Medicine.

While all ILC2 cells come from the same developmental pathway and start out looking the same, they start to diverge once they take up residence in an organ. His lab wanted to understand the signals that drive the cells to become specifically adapted to their host environment.

“ILC2 cells have tiny little antennas that allow them to recognize what’s happening in an organ, but if you look closely at ILC2s across tissues, these antennas are all a little bit different in each organ,” says Mortha, who is a member of the Emerging & Pandemic Infections Consortium.

“Which signals determine the set of antennas an ILC2 will be using in an organ? Knowing this could explain why ILC2 respond distinctly in the lung or the intestine.”

Using mouse models, the researchers proved that the organ itself was directing the immune cells to change their appearance by altering which proteins, or antennas, they displayed on their surface. In one key experiment, the researchers transplanted ILC2 cells from the lung into the gut and vice versa. They observed that, in response to organ-specific cues, the transplanted cells took on characteristics associated with their new home.

The researchers also identified the nature of these signals and where they came from. Their findings uncovered the Notch signalling pathway as a key regulator of ILC2 specialization in the gut. The pathway is triggered by the production of a signalling molecule called Delta-like 1 (DLL1) by mucus-secreting cells in the intestinal barrier lining. DLL1 attaches to Notch receptors on the surface of ILC2 cells which, in turn, activates the intermediary regulator RBPJ, a protein that turns genes on or off in ILC2s and determines their tissue identity. The researchers showed that in the absence of RBPJ, ILC2 cells did not make key surface proteins that, under normal conditions, would allow them to respond to a parasitic infection in the gut. Instead, the gut ILC2s resembled ILC2 cells from the lung.

“This is the first demonstration that ILC2s are actually adapting to the organs that they enter and call home,” says Mortha.

He says that by defining the communication pathway driving ILC2s to adapt to the gut, their work lays the foundation for targeted genetic and pharmacological interventions that can not only fine-tune how these cells respond to infections, but also subdue their activity in cases of chronic inflammatory conditions.

According to Mortha, autoinflammatory conditions can arise when immune responses that normally target an infection get misdirected toward your own body. In such cases, having the tools to quiet hyperactive immune cells in the specific tissue where they are causing damage could be a more effective way to manage these conditions with fewer side effects.

“Our work could inform how to manage diseases in an organ-specific way, instead of using a sledgehammer method that acts on the entire body,” says Mortha.

This research was supported by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, JP Bickell Foundation, Canadian Allergy, Asthma, and Immunology Foundation, and Sanofi Canada.