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Bidirectional metabolic signaling in follicular helper T cell differentiation

Award Number: R01AI150241
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: 09/19/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Bidirectional metabolic signaling in follicular helper T cell differentiation - Program Summary/Abstract Follicular helper T (Tfh) cells provide essential help for B cells and high-affinity antibody production, thereby linking cellular and humoral immunity. While much emphasis has been placed on immune receptors (e.g. ICOS) and transcription factors (e.g. Bcl6) required for Tfh differentiation, how signals are transduced from receptors to transcriptional and biological responses remains poorly defined. Emerging studies reveal nutrient signaling and metabolic reprogramming as fundamental processes underlying the growth and fate decisions of activated lymphocytes. However, many questions remain regarding the specific metabolic pathways important for T cell fate decisions (rather than as a consequence of changes in cellular phenotypes), and how immune signals intersect with nutrient inputs and metabolic programs. For instance, compared with our knowledge on glycolytic or Warburg metabolism, the function and regulation of mitochondrial metabolism are much less clear. We establish that mTOR acts as a key driver of Tfh differentiation by coordinating T cell receptor and ICOS signaling and glucose metabolism. Through unbiased screens, mouse genetic models and systems biology approaches in our preliminary studies, we also revealed crucial roles of nutrient signaling and mitochondrial metabolism in Tfh responses. Our central hypothesis is that the interplay between mTORC1 and nutrient signaling pathways and mitochondrial metabolic programs orchestrates bidirectional metabolic signaling and Tfh differentiation. Specifically, we will (1) identify the mechanisms that integrate nutrient and immune signals in Tfh responses, and (2) establish mitochondrial function and metabolic heterogeneity in Tfh responses. Importantly, despite the emerging interest in immunometabolism, how nutrient signaling and mitochondrial metabolism contribute to T cell function remains poorly understood. Building upon our expertise and innovation that combine genetic and systems biology approaches, we will address fundamental questions of immunometabolism and Tfh biology. Insights gained from this application may significantly impact our understanding of Tfh biology and manifest legitimate therapeutic opportunities.


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: 2026 ( Subtotal = $0 )
2026	2023	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	12/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $536,278 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	8/11/2023	NON-COMPETING CONTINUATION	$536,278
														Subtotal = $536,278

Issue Date FY: 2022 ( Subtotal = $536,278 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	4	8/19/2022	NON-COMPETING CONTINUATION	$536,278
														Subtotal = $536,278

Issue Date FY: 2021 ( Subtotal = $536,278 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	3	8/10/2021	NON-COMPETING CONTINUATION	$536,278
														Subtotal = $536,278

Issue Date FY: 2020 ( Subtotal = $536,278 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	8/6/2020	NON-COMPETING CONTINUATION	$536,278
														Subtotal = $536,278

Issue Date FY: 2019 ( Subtotal = $536,278 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	1	9/19/2019	NEW	$536,278
														Subtotal = $536,278

Grand Total All Awards = $2,681,390

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Bidirectional metabolic signaling in follicular helper T cell differentiation

Award Number: R01AI150241

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: 09/19/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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