Wednesday, January 28, 2026 1/28/2026

Nutrient sensing and lysosomal signaling in regulatory T cells and immune tolerance

Award Number: R01AI150514
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: 09/19/2014
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Nutrient sensing and lysosomal signaling in regulatory T cells and immune tolerance - Program Description/Abstract Regulatory T cells (Tregs) are central mediators of immune tolerance, but can also be a major hurdle to tumor immunity and immunotherapy. Tregs respond to TCR stimulation in the periphery and develop into activated Tregs (aTregs), whose function is important for tissue homeostasis in non-lymphoid organs and immune regulation in the tumor microenvironment. In addition to TCRs, microenvironment-derived signals, especially nutrients, have emerged as important regulators of T cell activation and differentiation, although the functional importance of nutrients in Tregs and whether and how they signal are unclear. We have a long-standing interest in understanding mTORC1 signaling in adaptive immunity and Treg biology. Our previous work has centered upon understanding the immune functions of mTORC1. How upstream signals regulate mTORC1 to shape Treg activation programs and tissue and tumor-specific responses remain poorly understood and will be the focus of this renewal application. To this end, we performed an unbiased, genome-wide screen for regulators of mTORC1 in Tregs, and identified the small G proteins RagA and Rheb1 among the top-ranking positive regulators of mTORC1 activity. Treg-specific deletion of RagA led to mild TH1-associated autoimmune responses, while loss of both RagA and the partially-redundant RagB resulted in the development of a fatal, Scurfy-like inflammatory disorder. Mechanistically, we found that RagA/B linked amino acids to mTORC1 activation and the generation of aTregs. Furthermore, we identified the functional importance of Rheb1 and its homolog Rheb2 in aTreg generation, and the interplay of RagA/B with Rheb and lysosomal signaling. We hypothesize that amino acids signal via RagA/B and interplay with Rheb and lysosomal signaling to license mTORC1 activation for functional programming of aTreg generation and suppressive activity. Aim 1. Establish the effects and mechanisms of RagA/B signaling in aTreg generation and function. Aim 2. Identify the integration of amino acid signals by TSC–Rheb and RagA/B in Tregs. Aim 3. Define lysosomal signaling and reconstruct mTORC1 signaling circuits in Tregs. We predict our studies will establish a new paradigm in Treg biology and mechanisms of mTORC1 regulation, with the potential to translate into innovative strategies to target cancer and other diseases.


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	10	12/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $448,750 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	10	8/14/2023	NON-COMPETING CONTINUATION	$0
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	10	8/11/2023	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

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	9	8/18/2022	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	8	8/10/2021	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2020 ( Subtotal = $448,750 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	7	8/6/2020	NON-COMPETING CONTINUATION	$448,750
														Subtotal = $448,750

Issue Date FY: 2019 ( Subtotal = $448,750 )
2019	2019	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	6	9/19/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$448,750
														Subtotal = $448,750

Grand Total All Awards = $2,243,750

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Nutrient sensing and lysosomal signaling in regulatory T cells and immune tolerance

Award Number: R01AI150514

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: 09/19/2014

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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