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Principal Investigator: Gregory Seumois
Organization: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $487,917
Funding agency: National Institute of Allergy and Infectious Diseases
Disease associated with allergies such as asthma are a rising health problem with no current curative
solutions. CD4+ helper T cells (TH) that respond to common allergens play an important role in driving airway
inflammation in asthma.
To better understand the diversity of T cell subsets in allergy and asthma, we analyzed the single-cell
transcriptome of ~50,000 house dust mite (HDM) allergen-reactive TH cells from asthmatics and non-
asthmatics, with and without HDM allergy. From our analysis, besides canonical clusters of cells such as TH2,
TH17, and TH1, we identified a novel subset of allergen-reactive TH cells characterized by an IFN responsive
gene signature that we called THIFNR cells (Seumois et al. Science Immunology, 2020).
Proportions of THIFNR cells were significantly increased in nonallergic individuals compared to allergic
patients, suggesting an allergen-specific host specific response even in non-allergic individuals. Moreover, the
exclusive presence of the allergen-reactive TH2 cells in the allergic patients suggests a protective role (anti-TH2
response) of the THIFNR cells in the non-allergic patients with exposure to allergen.
This potential protective role was reinforced by our in vitro studies showing that TNF-related apoptosis-
inducing ligand (TRAIL) produced by THIFNR cells directly inhibits T cell activation triggered by TCR
engagement. In follow-up studies, we found THIFNR cells among viral-reactive TH cells directed towards Flu or
SARS-CoV2, suggesting a broader role of those cells in immune responses. Also, we found THIFNR cells as a
stable TH subset in a large cohort of healthy individuals. Because of the recent discovery of THIFNR cells, very
little is known about their origins, differentiation, phenotype, and function. We hypothesize that these THIFNR
HDM-reactive T cells could play a role through TRAIL engagement in dampening TH2 inflammation in allergy
and asthma.
In Aim 1, we will utilize Interferon-stimulated response element (ISRE) reporter mice and T cell-specific
interferon receptor 1 (IFNAR1) knockout mice to determine the importance of THIFNR cells in controlling
allergic airway inflammation in asthma models. In Aim 2, we will perform single-cell ATAC-seq profiling to
identify transcription factors that may be involved establishing and maintaining the epigenetic state of THIFNR
cells. Finally, we will test functionally those TF by using shRNA knockdown experiments. Overall, studies in
this program will improve our understanding of how THIFNR cells are generated in vivo and how they interact
with other CD4+ T cells subsets like TH2 cells to curtail allergic airway inflammation in asthma models.
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