New Nature research answers controversy and provides new insights into the immune mechanism of inflammatory diseases

Innate lymphoid cells are a family of recently discovered white blood cells found in the skin, gastrointestinal tract, respiratory tract, and other barrier tissues
of the body.
A new study led by researchers at Weill Cornell Medical College shows that Group 2 innate lymphoid cells (ILC2) play a vital role
in protecting these tissues from parasitic infections and damage associated with allergic inflammation and asthma.

This finding resolves the controversy
that ILC2 may have redundancy with other cells in the body.
The study also suggests that a unique set of regulatory networks controlled by gut neurons may be a viable target for future drug therapies to combat chronic inflammatory diseases, including asthma, allergies and inflammatory bowel disease (IBD).

The study, published Nov.
2 in the journal Nature, shows that although ILC2 has many functional similarities to immune cell T helper type 2 cells (Th2 cells), the latter cell type does not adequately compensate for the loss of ILC2's protective
response to intestinal parasitic infections and intestinal inflammation.
To underscore the clinical relevance of the study, the researchers found evidence that
human ILC2 responds in a similar way to mouse ILC2.

"This advances our understanding of the complexity of the immune system and provides a potentially new set of targets for our future therapies," said the study's senior author, Dr.
David Artis, director of the Jill Roberts Institute for Inflammatory Bowel Diseases, director of the Friedman Center for Nutrition and Inflammation, and Michael Coles Professor
of Immunology at Will Cornell Medical College.

ILC2 is part of a family of innate lymphoid cells that was discovered
by multiple research groups only about 12 years ago.
Innate lymphoid cells are found in barrier tissues and are often considered sentinels and first responders
against various infections.
But scientists also recognize that ILCs may be the key to understanding common inflammatory and autoimmune diseases, such as asthma and IBD
.

ILC2 and Th2 cells are thought to have evolved, at least in part, to protect the body from parasitic infections, biting insects, and other environmental factors
.
When triggered by these types of challenges, both contribute to the formation of so-called type 2 immune responses
.
These similarities led the researchers to believe that ILC2 is almost functionally identical, but ILC2 focuses on earlier, more local responses, while T cells travel and flow more through the bloodstream, concentrating on multiple tissues
that need it.
However, in the new study, the researchers found that ILC2 has an important immune role, not as a superfluous
role as a type 2 immune response.

When ilc2 and Th2 cells are activated by a helminth infection, they both produce a tissue-protective protein called biregulatory protein (AREG).

To determine whether Th2 cells could compensate for the loss of this protein in ILC2, the researchers engineered mice to selectively delete AREG production in ILC2 and not in Th2 cells
.
They found that these mice were more susceptible to intestinal parasitic infections
due to a reduced anti-parasitic immune response compared to mice with normal ILC2.
Mice lacking ILC2 AREG were also more susceptible to intestinal damage
caused by inflammation.

"This finding clarifies that ILC2 plays a major role in this tissue-protective response — without them, this response is inadequate," said
Hiroshi Yano, Ph.
D.
, co-first author of the study and a postdoctoral research assistant in Artis' lab.

Elucidating the functional importance of a major immune cell type is a major achievement in basic immunology, and the results of this study also have clinical
applications.
The researchers showed that whether it is helminth infection or inflammatory bowel injury, the immune response of ILC2 is selectively controlled
by signaling molecules produced by intestinal neurons.
Injecting this molecule into mice with experimental intestinal inflammation boosted AREG production in ilc2 and protected the animals from intestinal damage
.
Preliminary experiments with intestinal ILC2 extracted from patients with inflammatory bowel disease have shown that this molecule can also enhance the protective response
of human cells.
Dr.
Artis said the findings suggest that neurons in the gut communicate with ILC2, producing a protective response that other immune cells cannot replace, thus providing new therapeutic opportunities
.