# Regulation of T cell-derived cytokines in allergic airway inflammation

> **NIH NIH F30** · YALE UNIVERSITY · 2021 · $30,846

## Abstract

Project Summary
The increasing prevalence of asthma over the past few decades signals an urgent need to understand disease
pathogenesis and to develop more effective therapeutics. High affinity IgE plays a central role in the disease by
mediating mast cell and basophil degranulation, which releases chemical mediators responsible for asthma
exacerbation. T follicular helper (Tfh) cells promote the relevant high affinity antibodies for a given immune
response through the cytokines they secrete. Tfh cell-derived IL-4 is required to induce high affinity IgE in
response to allergens. However, IL-4 has also been considered a canonical Tfh cell cytokine, produced even
during microbial immunizations that do not elicit IgE. Such studies largely rely on the use of an IL-4 cytokine
reporter that indicates activation of Il4 transcription but not necessarily transcript stability or translation. Our lab
has established murine models of Alternaria-induced allergic airway inflammation (AAI), which involves high
affinity IgE production, as well as lipopolysaccharide (LPS)-induced lung inflammation, which does not. Using
these two models, I observed Il4 mRNA expression in Tfh cells from both conditions; in contrast, I found that
only Tfh cells in AAI produce IL-4 protein. My preliminary data suggest that Il4 mRNA in Tfh cells from AAI is
more stable than that from LPS-induced inflammation, uncovering a post-transcriptional regulatory mechanism
that governs IL-4 production in Tfh cells. My overall hypothesis is that post-transcriptional regulation of Il4 is a
checkpoint dictating the high affinity IgE-promoting capacity of Tfh cells. My proposal therefore suggests a new
paradigm for the regulation of IL-4 protein production in Tfh cells and the molecular basis of IgE-mediated AAI.
My first aim is to identify the mRNA regulatory sequences responsible for Il4 post-transcriptional
regulation in Tfh cells during AAI versus LPS-induced lung inflammation. To accomplish this, I will clone
Il4 expression constructs mutated in regulatory sequences to determine the effect on Il4 mRNA stability, IL-4
protein production, and high affinity IgE responses. My second aim is to evaluate the role of an RNA-binding
protein (RBP) on IL-4 production in Tfh cells during AAI. To do this, I will map RBP-Il4 binding sites, mutate
these binding sites in Il4 expression constructs, and evaluate the effect of such mutations on Il4 mRNA stability,
IL-4 protein production, and high affinity IgE responses. If successful, this project will define a previously
undescribed mechanism of IgE regulation in asthma while also elucidating the immunologic rules that prevent
the inappropriate induction of IgE in non-allergic responses. Such findings will offer valuable insight into new
strategies for blocking IgE development in asthma and other allergic diseases.

## Key facts

- **NIH application ID:** 10410348
- **Project number:** 5F30HL149151-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jennifer S Chen
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,846
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410348

## Citation

> US National Institutes of Health, RePORTER application 10410348, Regulation of T cell-derived cytokines in allergic airway inflammation (5F30HL149151-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10410348. Licensed CC0.

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