# Lung-Resident Memory Th2 cells in Asthma - New Therapeutic Targets

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $482,845

## Abstract

Asthma is one of the most common chronic diseases and it is still on the rise with a prevalence estimated at 8-
9% of the U.S. population (~40 million) with an estimated cost of $50 billion/year in the US. New therapeutic
approaches are needed that offer the potential for a long lasting cure, instead of merely suppressing chronic
lung inflammation. Allergic asthma is the most common asthma endotype and is thought to be driven in large
part by a type 2 airway immune response to inhaled allergens. Defining how memory CD4+ T helper type 2
(Th2) cells initiate an airway recall response to aeroallergens has the potential to offer new therapeutic
approaches to treat allergic asthma. Recently, a new paradigm in memory T cell biology has emerged in which
tissue-resident memory T cells (Trm) persisting in non-lymphoid tissue are critical for initiating antigen-specific
recall responses in peripheral tissue. Trm are a unique subset of memory T cells that are anatomically
positioned and transcriptionally programmed to initiate the tissue amnestic response to antigen. During periods
of disease quiescence, approximately 5-10% of effector Th2 cells driving allergic asthma give rise to tissue-
resident memory Th2 cells (Th2-Trm) that are retained in the lung and are thus poised to respond upon
allergen re-exposure. While Th2-Trm have been described in a murine model of asthma, how they promote
allergic inflammation is unclear. The objective of this proposal is to define the mechanisms whereby Th2-Trm
persisting in the lung orchestrates a recall response to inhaled allergens. Our central hypothesis is that Th2-
Trm ignite allergic airway inflammation via a rapid and enhanced response to cognate antigen in the airway
and the ability to recruit circulating Th2 cells (Th2-Tcr) to the sites of antigen presentation in the lung.
Mechanistically, we hypothesize that Th2-Trm co-localize with DCs expressing the Th2 cell-attracting
chemokine CCL17 and after allergen re-challenge rapidly produce type 2 cytokines that initiate allergic
inflammation and markedly enhance DC expression of CCL17. This increased CCL17 expression recruits Th2-
Tcr cells from the blood to sites of antigen presentation where Th2-Tcr receive a “second touch” from cognate
antigen loaded and activated DCs and become fully competent to amplify allergic inflammation. We propose to
use innovative experimental systems to define the function of Th2-Trm, including parabiosis, a novel CCR4
ligand −CCL17 and CCL22− dual reporter mouse, and single cell RNA-seq analysis of murine lung and human
airway mucosal CD4+ T cells obtained via bronchial brushing. Specifically, we propose: (1) To define the
function of lung-resident Th2-Trm in regulating recurrent allergic airway inflammation in murine models and to
define the transcriptional phenotype of murine and human lung Th2-Trm and Th2-Tcr; and (2) To define the
role of CCL17 in regulating Th2-Trm and Th2-Tcr cell localization and function and to define the functi...

## Key facts

- **NIH application ID:** 9823833
- **Project number:** 5R01AI040618-23
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ANDREW D LUSTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,845
- **Award type:** 5
- **Project period:** 1997-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823833

## Citation

> US National Institutes of Health, RePORTER application 9823833, Lung-Resident Memory Th2 cells in Asthma - New Therapeutic Targets (5R01AI040618-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9823833. Licensed CC0.

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