# Preconceptual paternal allergen exposure, offspring asthma, and pulmonary gamma/delta T cell function

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $238,500

## Abstract

The “Developmental Origin of Health and Disease” (DOHaD) hypothesis posits that early life exposures
(nutritional, environmental, inflammatory) influence offspring susceptibility to a number of non-communicable
diseases. Allergic asthma, a disease affecting >300 million people, continues to increase in prevalence.
Consistent with the DoHAD hypothesis, maternal and paternal exposures can influence both risk and severity of
offspring asthma. Maternal exposures to environmental factors can influence offspring asthma by modifying the
epigenome in offspring T cells and dendritic cells. In contrast, while specific paternal exposures (tobacco smoke,
employment in specific occupations) alter offspring asthma risk in humans, the cell types impacted in offspring
are unknown. Our novel preliminary data demonstrate that pre-conceptual paternal HDM exposure to the
allergen house dust mite (HDM) is associated with a reduced asthma severity and increased recruitment of Rorgt-
expressing gd T cell populations in offspring, and that depletion of offspring gd T cells abrogates the protective
effect of paternal allergen exposure. While paternal exposures have been demonstrated to influence offspring
behavior, and/or development of metabolic dysfunction in animal models, our innovative preliminary data are the
first to demonstrate that paternal exposures to allergens influence chronic inflammatory responses in offspring.
As gd T cell depletion reversed the protective effects of paternal allergen exposure, we hypothesize that paternal
HDM exposure reduces offspring asthma severity by altering the phenotype and function of Rorgt-expressing gd
T cell populations present in the lung. This innovative hypothesis will be tested in two independent, yet related
specific aims. Aim 1: To determine if Rorgt-expressing gd T cells are necessary and sufficient to reduce
airway hyper-responsiveness in offspring of HDM-exposed fathers, we will 1) delete Rorgt selectively in gd
T cells in offspring of allergen-exposed fathers, and 2) adoptively transfer lung Rorgt+ gd T cell populations
isolated from offspring of control or allergen-exposed fathers into the lungs of control mice. The complete asthma
phenotype will be assessed to determine if pulmonary gd T cells are necessary and/or sufficient mediators of
paternal allergen-exposure-mediated protection from offspring asthma. Aim 2: Construct the gene regulatory
networks (GRNs) governing asthma-protective lung gd T cells. To this end, lung gd T cells from offspring of
control and allergen-exposed fathers will be isolated prior to, and after allergen sensitization, and profiled using
scRNA-seq and scATAC-seq for GRN construction. The GRN will identify how TFs utilize enhancers and
orchestrate gene expression patterns correlated with asthma protection. We will determine whether the asthma-
protective role of gd T cells is due to changes in subset abundances and/or altered functionality. An understanding
of the cellular and molecular mec...

## Key facts

- **NIH application ID:** 10300217
- **Project number:** 1R21AI156185-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Ian Paul Lewkowich
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $238,500
- **Award type:** 1
- **Project period:** 2021-06-11 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10300217

## Citation

> US National Institutes of Health, RePORTER application 10300217, Preconceptual paternal allergen exposure, offspring asthma, and pulmonary gamma/delta T cell function (1R21AI156185-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10300217. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*