# Tuft cell effector functions in the small intestine

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $549,015

## Abstract

Project Summary/Abstract
Helminths, allergens, and certain protists all stimulate a type 2 immune response and contribute significantly to
the global disease burden. Currently, more than 1 billion individuals worldwide are infected with helminths, and
the rising incidence of allergic disease represents an emerging epidemic. The sensing and signaling events
that initiate type 2 immunity remain poorly understood, but in the small intestine they require epithelial tuft cells.
Tuft cells regulate a tuft-ILC2 circuit in which tuft cell-derived IL-25 activates group 2 innate lymphoid cells
(ILC2s) in the underlying tissue. ILC2s secrete the canonical type 2 cytokines IL-5, -9, and -13, which
collectively drive hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. IL-13 also
promotes a feed-forward response by inducing tuft and goblet cell hyperplasia. The immune function of tuft
cells requires a chemosensory pathway and recent studies identified the microbial metabolite succinate as an
intestinal tuft cell ligand that is sufficient to activate the tuft-ILC2 circuit. Tuft cells therefore act as IL-25-
secreting immune sentinels, but several lines of evidence support the central hypothesis of this proposal that
additional tuft cell effector functions must exist: (1) Tuft cells express IL-25 constitutively, but the feed-forward
tuft-ILC2 circuit is only activated in the presence of helminths or protists, suggesting additional activating
signals; (2) the initiation of tuft cell hyperplasia after immune sensing has occurred suggests tuft cells
contribute to the effector stages of type 2 immunity; and (3) helminth clearance is more delayed in tuft cell-
deficient mice than in mice that lack only IL-25. The goal of this proposal is therefore to discover and
characterize novel tuft cell effector functions in the small intestine. Using a combination of innovative in vitro
assays and in vivo helminth infection of genetically modified mouse strains, we propose to test the regulation
and function of tuft cell-derived IL-25, leukotriene C4, and acetylcholine. These studies should identify novel
targets for therapeutic intervention in both helminth infection and allergic disease.

## Key facts

- **NIH application ID:** 10086844
- **Project number:** 5R01AI145848-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jakob H. von Moltke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $549,015
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086844

## Citation

> US National Institutes of Health, RePORTER application 10086844, Tuft cell effector functions in the small intestine (5R01AI145848-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10086844. Licensed CC0.

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