# The Origin and Role of Pulmonary ILC2 Subsets in Anti-Helminth Immunity

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2020 · $553,233

## Abstract

Project Summary
The World Health Organization estimates that soil transmitted helminths infect 1 in 4 people worldwide.
Protection or clearance of these parasitic worms requires the initiation of a type-2 immune response. Productive
type-2 immunity and worm clearance are dependent on three key cytokines: interleukin (IL)-4, IL-5, and IL-13.
Group 2 innate lymphoid cells (ILC2) represent an important source of type-2 cytokines. Specifically, ILC2 cells
sense damaged mucosa and act as early orchestrators anti-helminth immunity. Currently, much of our
understanding regarding the role of ILC2 cells in anti-helminth immunity stems from work focused on tissue-
resident ILC2 or natural ILC2 (nILC2) cells. However, we and others have recently described a second subset
of migratory ILC2s, termed inflammatory ILC2, (iILC2) cells. The distinct phenotype, timing, origin, and function
of these distinct ILC2 subsets suggests that iILC2 cells serve a unique role in anti-helminth immunity.
 The studies outlined herein will address the following critical gaps in our knowledge: 1) The origin(s) of
iILC2 cells, which remains in debate. 2) How iILC2 cells transit to the lung and the extent they enter the
parenchyma during infection is unknown. 3) The impact that iILC2 cells have on tissue-resident ILC2 population
remains unclear, and their role in long-term protection against helminths has not been explored. The aims below
will address these knowledge gaps by testing the central hypothesis that migratory iILC2 cells, originating from
small intestine or bone marrow precursors, acquire an nILC2 phenotype upon entry into the lung and contribute
significantly to barrier immunity after repeated helminth infection. Aim 1: Determine iILC2 origin and tissue
heterogeneity during helminth infection. Aim 2: Elucidate the mechanism of iILC2 migration and diapedesis into
the lung. Aim 3: Determine the extent that iILC2 cells contribute to the tissue-resident ILC2 pool after sequential
N. brasiliensis exposure. These aims are both innovative in concept (by challenging the current dogma
surrounding iILC2 cells) and approach (by using unique reporter mice and genomic systems to track the fate and
function of iILC2 cells). This proposal is significant because understanding of the origin of iILC2 cells, how
they egress and migrate to inflamed mucosa, and their contribution to the long-term tissue-resident ILC2
population in the lung significantly advances our understanding of ILC2 biology. Filling these key gaps in our
knowledge will establish the role of iILC2 cells as both critical first responders to helminth infection and also
identify the mechanisms contributing to their role in long-term barrier maintenance and integrity.

## Key facts

- **NIH application ID:** 10131483
- **Project number:** 1R01AI156901-01
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Richard Lee Reinhardt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $553,233
- **Award type:** 1
- **Project period:** 2020-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131483

## Citation

> US National Institutes of Health, RePORTER application 10131483, The Origin and Role of Pulmonary ILC2 Subsets in Anti-Helminth Immunity (1R01AI156901-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10131483. Licensed CC0.

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