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A novel CD4+ T cell subset associated with allergy protection

Award Number: R21AI173884
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/11/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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A novel CD4+ T cell subset associated with allergy protection - 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 in vivo and to translate findings to the clinic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	3	4/3/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$21,662
2025	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	4/3/2025	NON-COMPETING CONTINUATION	-$21,662
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $242,111 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	6/6/2024	NON-COMPETING CONTINUATION	$228,750
2024	2024	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	3	8/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$217,111
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	2	8/1/2024	NON-COMPETING CONTINUATION	-$203,750
														Subtotal = $242,111

Issue Date FY: 2023 ( Subtotal = $274,500 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	7/11/2023	NEW	$274,500
														Subtotal = $274,500

Grand Total All Awards = $516,611

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A novel CD4+ T cell subset associated with allergy protection

Award Number: R21AI173884

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/11/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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