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Principal Investigator: Gregory Seumois
Organization: LA JOLLA INSTITUTE FOR IMMUNOLOGY
Fiscal Year: 2024
Award: $25,000
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
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 define the functional properties of THIFNR cells. We will perform co-culture experiments to test
the ability of THIFNR cells to inhibit proliferation and function of TH2 cells in a TRAIL-dependent manner. In Aim
2 we will determine optimal conditions to induce differentiation of THIFNR cells in vitro and compare their
functional properties with those generated in vivo. Finally, in Aim 3, we will determine if HDM-reactive THIFNR
cells show persistence and plasticity in vivo. We will perform single-cell TCR sequencing of HDM-reactive
THIFNR cells and other memory CD4+ T cell subsets isolated from longitudinally collected blood samples of HDM
allergic and non-allergic subjects. By comparing TCR repertoire in longitudinal samples, we will assess
persistence of THIFNR cells in vivo. Overall, functional studies in this R21 program will provide important insights
into this novel CD4+ T cell subset; and form the basis of a future R01 application to conduct studies translating
findings to the clinic.
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Proteins><Dermatophagoides Allergens><Development><Disease><Disorder><Encephalon><Endogenous Interferon Beta><Exploratory/Developmental Grant><Exposure to><Extrinsic asthma><Fibroblast Interferon><Follow-Up Studies><Followup Studies><Frequencies><Future><Genomics><Grant><Grippe><Health><Heterogeneity><House Dust Mite Allergens><House Dust Mites><Housedust Mites><Human><Hypersensitivity><IFN><IFN-Beta><IFN-β><IFNb><Immune><Immune response><Immunes><Immunological response><Immunology><In Vitro><Individual><Inflammation><Influenza><Interferon-beta><Interferon-β><Interferons><Ligands><Lung><Lung Respiratory System><Mediating><Modern Man><Natural Interferon Beta><Natural human interferon beta><PBMC><Pathogenicity><Patients><Peripheral Blood Mononuclear Cell><Persons><Phenotype><Play><Population><Process><Production><Proliferating><Property><Proteins><Pyroglyphidae><R21 Mechanism><R21 Program><Receptor Protein><Regulatory T-Lymphocyte><Research><Rhinitis allergic atopic><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Science><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Surface><T cell receptor repertoire sequencing><T cell receptor sequencing><T-Cell Activation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-cell 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