# Type III interferon Control of Mucosal Immunity

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $622,835

## Abstract

PROJECT SUMMARY
The gastrointestinal tract is composed of a single layer of epithelial cells that separates the inside of the body
from a complex and vast community of harmless micro-organisms (the microbiome) that live in the intestine and
provide essential functions to the host. Underneath the epithelial lining is the largest population of immune cells
in the mammalian body that serves as a critical monitor of these micro-organisms sensing the presence of
potential disease-causing pathogens. Inflammatory bowel disease (IBD) is thought to result when the immune
system inappropriately responds to the microbiome with an aggressive attack resulting in intestinal inflammation
and damage. The immune signals that recognize and respond to bacterial and viral components of the
microbiome are incompletely understood. Interferons (IFN) play a critical role in this process with diverse
activities but are most known for their inherent anti-viral activities. IFNs are divided into three classes: type I IFNs
(that comprise IFNα, β and others), type II IFNs (IFNγ) and the more recently identified type III IFNs or IFNλs.
Most studies investigating the relationship of IFNs and IBD have focused on the relevance of type I IFNs. The
cellular targets of IFNλs are much more limited and defined, compared to those of type I IFNs, because the
specific receptor for IFNλ, IFNLR1, is almost exclusively expressed in epithelial cells. We have recently
demonstrated that IFNLR1 is also expressed on neutrophils. More importantly, we have demonstrated in mice
that: 1) IFNλ targets neutrophils; 2) IFNλ blockade enhances inflammation; 3) commensal enteric viruses
regulate IFNλ-dependent responses; and 4) exogenous IFNλ administration suppresses intestinal inflammation.
Further support of a critical role for IFNλ in mucosal homeostasis beyond murine biology comes from our recent
identification of an infant with very early onset IBD (VEOIBD) that has homozygous damaging mutations in two
IFNλs. Collectively, these findings serve the basis of our hypothesis that IFNλ is a critical modulator of mucosal
homoeostasis in mice and humans and may be an attractive therapeutic agent for IBD. In this project, we will
benefit from the joint expertise of two co-principal investigators (Snapper and Zanoni) and capitalize on a vast
compilation of conditionally targeted murine models, deep expertise in murine models of IBD, and relevant
patient-derived materials. We propose four aims where we plan: 1) to assess the protective and therapeutic role
of IFNλ in acute and chronic models of colitis; 2) to determine the cell population(s) that mediates IFNλ-
dependent colitis protection and therapeutic responses; 3) to assess the role of microbiota in IFNλ-dependent
regulation of intestinal inflammation and IFNλ-dependent therapeutic responses; 4) to assess how mutations in
human IFNλ alter mucosal homeostasis. Completion of the aims of this grant will aid in defining the precise
mechanisms by which IFNλs ...

## Key facts

- **NIH application ID:** 9989843
- **Project number:** 5R01DK115217-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Scott B Snapper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,835
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989843

## Citation

> US National Institutes of Health, RePORTER application 9989843, Type III interferon Control of Mucosal Immunity (5R01DK115217-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989843. Licensed CC0.

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