# Defining group 2 innate lymphoid cell lung niches

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $518,500

## Abstract

Project Summary/Abstract
Group 2 innate lymphoid cells (ILC2s) are tissue-resident lymphocytes with emerging roles in tissue
development, remodeling, and allergic disease. In the lung, ILC2s are key instigators of allergic asthma, yet
little is known about where ILC2s reside and how stromal interactions shape ILC2 development and function.
We have found that lung ILC2s reside in specific perivascular ‘niches’, where they intimately associate with a
mesenchymal cell subset that expresses the cytokines IL-33 and TSLP. The goal of this proposal is to
rigorously investigate the role and cross-talk of these ‘niche’ mesenchymal cells on ILC2 developmental
localization, function, and induction of type 2 immune responses. Based on our preliminary data, we propose
that niche perivascular mesenchymal cells impact ILC2 localization and function via the production of known
cytokine signals, including IL-33 and TSLP, as well as other novel pathways, providing a nidus for adaptive
Th2 immune responses. During inflammation, ILC2s cooperate with Th2 tissue-resident memory cells to cross-
regulate mesenchymal cell function and cytokine production. In Aim One, we will define how adult lung ILC2
‘niche-associated’ mesenchymal cells impact ILC2 activation and induction of adaptive type 2 immune
responses. Global deletion of niche mesenchymal cells impaired lung type 2 immune responses, and we
predict that cytokines such as IL-33 and TSLP, as well as other unknown factors, contribute to the activation of
ILC2 and the type 2 immune response. In Aim Two, we will characterize the stromal cells and signals that
govern the postnatal, developing ILC2 niche. Our preliminary data indicate the earliest ILC2 interact with and
require mesenchymal perivascular niche cells for optimal expansion. We will test the development of these
perivascular niches and their contribution to ILC2 localization and function in perinatal life, and how allergic
challenges in this period alter the developing niche. In Aim three, we will explore how ILC2 and tissue Th2 cells
cross-regulate niche mesenchymal cells. We have found that both ILC2, Th2, and IL-33 expressing
mesenchymal niche cells expand during helminth infection, and ILC2 are required for optimal expansion and
IL-33 expression by mesenchymal niche cells. Here we will test how ILC2-derived cytokines impact
mesenchymal niche function during both perinatal development and adult immune challenge. We expect that
signals from ILC2 dynamically regulate niche mesenchymal cell function and IL-33 expression to cause long-
lasting changes in tissue immune tone and predisposition towards subsequent allergic asthma. Together, we
use novel 3D imaging techniques, RNA-sequencing, and transgenic tools to answer a critical and unknown
question: how are ILC2 locally regulated at their lung niches? We anticipate these studies will have
fundamental implications for the control of ILC2 and type 2 allergic immunity in allergic asthma, and yield
insight into h...

## Key facts

- **NIH application ID:** 10241240
- **Project number:** 5R01HL142701-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ari B Molofsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $518,500
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241240

## Citation

> US National Institutes of Health, RePORTER application 10241240, Defining group 2 innate lymphoid cell lung niches (5R01HL142701-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241240. Licensed CC0.

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