# Trefoil factor proteins regulate inflammation and immunity

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $53,611

## Abstract

Parent Award (U01-AI125940)
Under normal circumstances, mucosal tissue damage caused by abrasions, chemicals, or biological
agents is quickly resolved, lest persistent inflammatory responses drive chronic disease. However, the
basic understanding of the immunoregulatory and regenerative mechanisms operating at the mucosal
interface remains fragmented and unclear. The central goal of this UO1 project is to uncover how Trefoil
factor family (TFF) proteins protect the gastrointestinal (GI) tract from injurious inflammatory responses
and drive host protection against metazoan parasites and pathogenic bacteria. Preliminary data shows
that we have discovered a previously unknown class of receptors for TFF2 and TFF3, a finding that
stands to radically impact the cellular and molecular understanding of how Trefoil factor responsiveness
in immune cells could govern the balance between tolerance and inflammation. Indeed, we
demonstrate that therapeutic administration of TFF3 resolves colitic inflammation and that TFF3
exposure promotes interleukin 10 family cytokine secretion from both human and mouse immune cells.
Taken together, the over-arching goal of this project is to bring forth a conceptual and technological
advance to the field of Trefoil factor biology. Our two main questions are: (1) whether Trefoil factors
function through cognate receptor-ligand interactions with members of the Leucine rich repeat and Ig
domain containing, Nogo receptor interacting protein (LINGO) family and (2) whether Trefoil factors
critically influence mucosal immune responses in the context of colitis or pathogen infection through
regulation of interleukin 10 family cytokine production. Our central hypothesis is that Trefoil factor 3
regulates mucosal IL-10 and IL-22 production through LINGO receptor-dependent mechanisms.
Experiments in specific aim 1 will establish whether TFF3 suppresses colitis via LINGO2 and/or
LINGO3-dependent mechanisms, those in specific aim 2 will define the pathway(s) and biological
importance for TFF3-dependent IL-10 production and experiments in specific aim 3 will define the
cellular and molecular mechanism(s) for TFF3-mediated regulation of IL-22. Through successful
completion of our project goals, we intend to stimulate broad interest and collaborative investigation of
Trefoil factors as an important part of the mechanisms that shape immunity, inflammation, and repair
at the mucosal interface.

## Key facts

- **NIH application ID:** 10136759
- **Project number:** 3U01AI125940-05S2
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** De'Broski R Herbert
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $53,611
- **Award type:** 3
- **Project period:** 2016-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136759

## Citation

> US National Institutes of Health, RePORTER application 10136759, Trefoil factor proteins regulate inflammation and immunity (3U01AI125940-05S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136759. Licensed CC0.

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