Tuesday, July 1, 2025 7/1/2025

Dissecting functions of IL-23-dependent inflammatory Th17 cells

Award Number: R01AI173277
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: 11/25/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Dissecting functions of IL-23-dependent inflammatory Th17 cells - Project Summary Although IL-17-producing T helper (Th17) cells are a major pathogenic contributor to autoimmune diseases, functional diversity undermines their potential as a prospective target for treating autoimmunity. Th17 cells are currently classified into homeostatic and inflammatory subpopulations. It was noted that inflammatory Th17 cells can be beneficial (anti-infection) and pathogenic (pro-autoimmunity). The distinction between homeostatic and inflammatory Th17 cells has been extensively studied. However, how to dissect the anti-infection and pro- autoimmunity functions of inflammatory Th17 cells is largely unknown. There is a critical need for this knowledge given serious infections and fatal outcomes observed in patients receiving general inhibitors of inflammatory Th17 cells (e.g. antibodies against IL-23). Herein, autoimmune and anti-infection subsets of inflammatory Th17 cells are for the first time distinguished experimentally. The objective of this grant is to elucidate the metabolic regulation discriminating autoimmune and anti-infection Th17 cells derived from murine models and human patients. The central hypothesis is that autoimmune and anti-infection Th17 subsets adopt distinct serine metabolic programming. The rationale is that determining the differences between autoimmune and anti-infection Th17 subsets will offer opportunities for novel therapeutics with substantially improved selectivity than the current regimens. The central hypothesis will be tested by pursuing three specific aims: 1) to determine the mechanism for regulating serine metabolism in the autoimmune Th17 subset; 2) to determine the mechanism by which serine regulates pathogenicity of the autoimmune Th17 subset; and 3) to determine the transcriptional and metabolic programming of Th17 cells from patients with inflammatory bowel disease (IBD). Under the first aim, autoimmune Th17 cells recovered from murine models will be used to measure intracellular serine and indicators of autoimmune pathogenicity with modulation of serine metabolic enzymes. For the second aim, biochemical approaches and murine models will be employed to evaluate the relationship between serine-induced intracellular methylation and pathogenic potential of Th17 cells. In the third aim, RNA-seq analysis will be performed to evaluate transcription profiles of Th17 cells from IBD patients. The research proposed in this application is innovative, because it focuses on the immunometabolic regulation discriminating anti-infection and autoimmune Th17 subsets, a heretofore-unexamined mechanism. The proposed research is significant because it is expected to provide novel opportunities to develop autoimmune Th17-selective therapeutics for autoimmune diseases. This would be extraordinarily important for patients that have been infected or exposed to certain pathogens, such as tuberculosis, since existing Th17 inhibitors cannot be used due to the risks of decreasing the patients’ control of the infection.


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	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $607,162 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	10/26/2023	NON-COMPETING CONTINUATION	$546,446
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	5/13/2024	NON-COMPETING CONTINUATION	$60,716
														Subtotal = $607,162

Issue Date FY: 2023 ( Subtotal = $568,301 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	2	6/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$538,489
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	003	1	8/29/2023	NEW	-$6,647
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	004	2	8/29/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,647
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	001	1	6/30/2023	NEW	-$527,000
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	1	11/25/2022	NEW	$556,812
														Subtotal = $568,301

Grand Total All Awards = $1,175,463

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Dissecting functions of IL-23-dependent inflammatory Th17 cells

Award Number: R01AI173277

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: 11/25/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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