# Regulation and function of innate lymphoid cells in the gut

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $423,750

## Abstract

PROJECT SUMMARY
Soil transmitted helminth infections remain one of the most neglected groups of infectious diseases and one of
the greatest public health challenges worldwide, with an estimated two billion people infected. Importantly,
recovery from helminth infection involves not only clearance of the parasite, but also successful repair of the
inflamed, damaged intestine in order to restore tissue protection and these mechanisms of tissue protection
are often conserved across non-infectious intestinal diseases. Thus, the development of successful immuno-
therapies against soil-transmitted helminth parasites requires a more comprehensive understanding of the
mechanisms that regulate both infection-induced immunity and intestinal tissue protection. This proposal will
interrogate the role of group 2 innate lymphoid cells (ILC2s) in promoting anti-helminth immunity and regulating
infectious and non-infectious intestinal tissue protection via activation of the amphiregulin (AREG)-epidermal
growth factor receptor (EGFR) pathway. In preliminary studies, we found that deletion of AREG resulted in
dysregulated immune responses, impaired worm expulsion and failed intestinal repair following helminth
infection. Critically, the importance of this pathway was not limited to pathogen infection, as AREG expression
was also elevated in a murine model of non-infectious intestinal damage, and disruption in AREG-EGFR
interactions resulted in exacerbated intestinal inflammation and impaired intestinal repair. We further identified
ILC2s as a key source of this growth factor and found that therapeutic transfer of ILC2s or AREG protein can
limit inflammation and promote tissue protection in mice. Despite these advances, the factors that regulate
intestinal AREG responses, the cell-intrinsic requirements for AREG expression, the downstream mechanisms
by which AREG influences epithelial cell responses, and whether differential AREG expression in humans is
associated with intestinal inflammation, all remain unknown. Employing new in vivo tools, this competitive grant
renewal will focus on delineating: (i) the signals and cell-intrinsic requirements for AREG in promoting immunity
to helminth infection and restoration of intestinal tissue protection, (ii) the mechanisms by which ILC2-AREG
regulates intestinal epithelial cell (IEC) progenitors to promote tissue protection, and (iii), whether therapeutic
delivery of rAREG can reverse established chronic intestinal tissue damage and inflammation and restore
tissue protection. We anticipate that defining the mechanisms by which the ILC2-AREG-EGFR pathway
regulates both intestinal immunity and tissue protection is critical for the design of new immunologic
intervention strategies to treat and prevent helminth infections and non-infectious inflammatory diseases such
as IBD.
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## Key facts

- **NIH application ID:** 9875424
- **Project number:** 5R01AI095466-08
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** David Artis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2011-08-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875424

## Citation

> US National Institutes of Health, RePORTER application 9875424, Regulation and function of innate lymphoid cells in the gut (5R01AI095466-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875424. Licensed CC0.

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