# ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $482,627

## Abstract

Project Summary / Abstract
This grant seeks to understand the role of Group 2 innate lymphoid cells (ILC2s) in sustaining an altered epithelial
interface that is crucial to the establishment of an aberrant remodeled niche that contributes to the persistence
of allergic pathology. The proposal is underpinned by publications supported in the prior grant, demonstrating
(1) a key role for tissue-elaborated epithelial cytokines in the activation of tissue type 2 immune cells, including
ILC2s; and (2) discovery of a feed-forward epithelial-ILC2 circuit in the intestines that drives goblet cell
hyperplasia and tissue hyperplasia, providing the impetus for uncovering similar circuitry in the respiratory
system. As shown by colleagues in Project 3, severe, drug-recalcitrant, asthma is populated disproportionately
with patients with relatively ‘fixed’ airway abnormalities associated with persistent mucus plugs; a significant
proportion of individuals also have recurrent nasal polyposis. Together with our discoveries in model animal
systems, our over-arching hypothesis is that dysregulated epithelial-ILC2 circuits in the respiratory tract,
including nasopharynx (NP), trachea and airways, underlie the presence of persistent niches where allergic
pathology is sustained. Using novel genetic tools in mice that permit exquisite dissection of such circuits, we
propose 3 Specific Aims that align within the overall goals of the PPG. First, we will define the ILC2 landscape
in mouse skin, NP, trachea and lung, where we have uncovered unsuspected diversity that has already been
extended to human studies by others in the PPG. Second, we will define the tuft cell landscape in NP and
trachea, since the critical role for this enigmatic epithelial cell was uncovered in our intestinal studies. We have
demonstrated tuft cell hyperplasia in human allergic polyps. Third, we will use a mouse model of skin
inflammation followed by lung allergen challenge to analyze the development of the epithelial-ILC2 circuit from
skin to NP to lung, and the role of these respective cells. These findings will be applied to human tissues
collected in Core B of this PPG and analyzed in Core C of this PPG to generate discovery in patients with severe
asthma. Together, this PPG will uncover dysfunctional cellular networks and niches that sustain allergic
immunopathology in the lung.

## Key facts

- **NIH application ID:** 10006351
- **Project number:** 5P01HL107202-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Richard M Locksley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,627
- **Award type:** 5
- **Project period:** 2012-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006351

## Citation

> US National Institutes of Health, RePORTER application 10006351, ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma (5P01HL107202-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006351. Licensed CC0.

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