Thursday, July 3, 2025 7/3/2025

Robust immune tolerance conferred by Foxp3 transcriptional regulation

Award Number: R01AI153138
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: 01/20/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

Group Awards By:

View Award Description

Robust immune tolerance conferred by Foxp3 transcriptional regulation - Robust immune tolerance conferred by Foxp3 transcriptional regulation Regulatory T (Treg) cells actively suppress self-destructive T cells that cause a variety of autoimmune diseases. Despite significant progress, Treg-based treatment is significantly constrained by limited methods to improve Treg suppressive capacity. We aim to dissect the mechanistic processes of Treg induction and lineage maintenance to uncover the factors and mechanisms conferring robust immune suppressive function. Treg cells are induced by the convergence of environmental cues delivered to differentiating T cells with considerable variations, resulting in stochastic Treg development. Besides, the DNA sequences of the genetic elements regulating Treg lineage identity also vary among individuals. Given the enormously diverse T cell antigen receptors (TCRs) and target specificities, Treg cells are induced with many uncertainties. Once committed, Treg fate is maintained for extended suppressive function by cell-intrinsic and -extrinsic factors that constantly fluctuate. All these uncertainties raise a question about how robust immune tolerance is conferred by Treg cells. Study of Treg master regulator Foxp3 offers a unique approach to address this question, because Foxp3 expression centers Treg fate determination and function. We hypothesize that an adequate buffering capacity conferred by efficient Treg development and lineage stability opposes the genetic variations and immune perturbations. To test this hypothesis, we examined the Foxp3 enhancers that dictate Treg induction and lineage stability. Individual Foxp3 enhancers were known to play stage-specific roles in Foxp3 induction or maintenance. However, mice bearing their individual mutations develop mild if any immune dysregulation despite significant defects in Treg development or lineage stability. To solve this mystery, we examined the epigenetic mechanisms mediating Foxp3 expression and hypothesize that Foxp3 enhancers coordinate to enable efficient Treg induction or stable lineage identity for adequate Treg buffering capacity. We generated new mouse strains to test our hypotheses and found that deletion of two interacting Foxp3 enhancers caused fatal autoimmune diseases accompanied with severe defects of Treg induction or lineage stability. This result together with other studies delineates a full spectrum of Treg buffering capacity acquired through coordinating Foxp3 enhancers. In the proposed study, we will fully uncover the immunological consequences of mice with severely reduced Treg induction or lineage stability. We will develop new algorithms and use single cell RNA sequencing to assess Treg repertoire diversity and lineage stability to infer Treg buffering capacity. We will also use our newly developed mouse genetic tools to determine the role of continuous thymic Treg induction in maintaining the Treg buffering capacity. Overall, our study will uncover a full spectrum of Treg suppressive capacity conferred by Foxp3 transcriptional regulation. It will improve our basic understanding of Treg-related autoimmune 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: 2025 ( Subtotal = $435,288 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	5	12/18/2024	NON-COMPETING CONTINUATION	$435,288
														Subtotal = $435,288

Issue Date FY: 2024 ( Subtotal = $448,750 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	001	4	5/20/2024	NON-COMPETING CONTINUATION	$44,875
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Allergy and Infectious Diseases Research	000	4	12/15/2023	NON-COMPETING CONTINUATION	$403,875
														Subtotal = $448,750

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	000	3	12/19/2022	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	2	12/16/2021	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	1	1/15/2021	NEW	$448,750
														Subtotal = $448,750

Grand Total All Awards = $2,230,288

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Robust immune tolerance conferred by Foxp3 transcriptional regulation

Award Number: R01AI153138

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: 01/20/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer