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Regulation of T cell memory in tissue immunity

Award Number: R01AI131703
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: 02/13/2018
PERIOD OF PERFORMANCE END DATE: 10/31/2029

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Regulation of T cell memory in tissue immunity - Program Summary/Abstract Tissue-resident memory T cells (TRM) are crucial for the frontline defense against pathogen infection and maintenance of tissue homeostasis. How T cells are fated for TRM development and targeted for residency in specific tissue sites remain poorly understood. The environmental cues that orchestrate metabolic adaptation for TRM development or maintenance are also unclear. These knowledge gaps represent substantial barriers to harnessing the full therapeutic potential of TRM cells in infectious disease and cancer. In our preliminary studies, using in vivo pooled CRISPR screening of mitochondria and lysosome-associated genes, we uncovered organelle signaling and metabolic processes shaping CD8+ TRM development. Specifically, three nutrient- dependent lysosomal signaling nodes, Flcn, Rag GTPases and Ragulator, potently inhibit TRM formation. Depleting these molecules or depriving amino acids activates transcription factor Tfeb, thereby linking nutrients to TRM programming. Further, Flcn deficiency promotes protective TRM responses against gastrointestinal pathogen infection. Mechanistically, Flcn restrains retinoic acid-orchestrated tissue recruitment and TGF-- mediated programming for TRM differentiation. A genetic interaction screen identified mitochondrial enzymes Me3 and Acss1 as putative targets that orchestrate metabolic adaptation and TRM formation under Flcn-associated lysosomal dysregulation, thereby establishing inter-organelle communication as a driver of this process. Our central hypothesis is that lysosomal signaling nodes integrate nutrient and immunological signals to program long-lived TRM cells, and targeting such signaling nodes is an innovative strategy to enhance the quantity and quality of TRM cells for tissue immunity. Our model represents a major advance in establishing an interplay between nutrients, organelle signaling and immunological pathways that dictates metabolic adaptation and tissue immunity and points to new avenues to improve TRM responses and tissue immunity. Aim 1. Establish the molecular and functional effects of lysosomal signaling nodes in TRM development. Aim 2. Define the intersection of nutrient and immunological signals for TRM differentiation and trafficking. Aim 3. Dissect mechanisms of metabolic and nutrient adaptation for TRM development. Despite the recent interest in immunometabolism, the function and mechanism of nutrient signaling and metabolic adaptation in TRM biology remain poorly understood. Building upon our expertise and innovation that combine T cell biology, mouse genetics, functional genomics and systems biology approaches, we predict our studies will establish a new paradigm by addressing fundamental questions in TRM biology and immunometabolism, with potentials for translation into innovative therapeutic strategies.


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 = $538,352 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	6	11/13/2024	COMPETING CONTINUATION	$538,352
														Subtotal = $538,352

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	8/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $448,750 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	1/25/2022	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2021 ( Subtotal = $448,750 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	4	1/21/2021	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2020 ( Subtotal = $833,411 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	3	8/6/2020	SUPPLEMENT FOR EXPANSION	$384,661
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	3	2/1/2020	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $833,411

Issue Date FY: 2019 ( Subtotal = $785,652 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	2	8/15/2019	SUPPLEMENT FOR EXPANSION	$336,902
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	2	1/7/2019	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $785,652

Issue Date FY: 2018 ( Subtotal = $448,750 )
2018	2018	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL MAILSTOP # 509	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	1	2/13/2018	NEW	$448,750
														Subtotal = $448,750

Grand Total All Awards = $3,503,665

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Regulation of T cell memory in tissue immunity

Award Number: R01AI131703

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: 02/13/2018

PERIOD OF PERFORMANCE END DATE: 10/31/2029

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