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IL-2R-dependent mechanisms in regulation of Treg homeostasis and autoimmunity

Award Number: R01AI148675
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: 12/10/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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IL-2R-dependent mechanisms in regulation of Treg homeostasis and autoimmunity - Studies initially pioneered in my lab and subsequent work by us and others established that IL-2 is an essential cytokine for the development, homeostasis and function of regulatory T cells (Tregs). We have further established in mouse models that low levels of IL-2R signaling effectively promote Treg but not T effector (Teff) cells. These findings have helped in the clinical translation of low-dose IL-2 as a Treg-targeted therapy for autoimmunity. Moreover, serious autoimmune-related side effects frequently occur as a consequence of checkpoint blockade during cancer immunotherapy, raising the possibility that low-dose IL-2 might alleviate these unwanted responses. In spite of this progress, we still have a poor understanding of the mechanisms by which IL-2 controls peripheral Tregs. Recently, we have developed several novel mouse models that vary IL- 2R signaling in Tregs. In one model (NOD-Y3), IL-2R signaling strength was lowered approximately 3-fold in Tregs in NOD mice, which accelerated diabetes. In another model, CD25 (IL-2Rα) was selectively abrogated in peripheral Tregs (CD25iKO mice), where all peripheral Tregs require IL-2R signaling for their survival. Our genome-wide expression studies suggests homeostasis of Tregs is impaired in the absence of IL-2R signaling due to decreased cholesterol biosynthesis that alters Treg metabolism and to lower expression of anti- apoptotic Bcl-2 that favors apoptosis. Although Treg suppressive function depends on IL-2R signaling, definitive data for this notion comes from studies where IL-2R signaling is impaired during thymic development. The suppressive activity of peripheral Tregs that have not responded to IL-2 remains unknown. Moreover, current models suggest that IL-2R signaling is primarily required for the homeostasis of resting or central Tregs (cTregs) while TCR signaling controls activated or effector Treg (eTregs). However, we found that the eTreg subset cannot survive without IL-2. Thus, the role of IL-2 for eTregs remains unclear. Our studies also indicate that reduced, but not absent, IL-2R signaling at the level of Tregs is sufficient to promote autoimmune- mediated diabetes in NOD mice. However, IL-2-dependent processes that are impaired within the islets of the pancreas to accelerate diabetes are poorly understood. We plan to build on these results and capitalize on our expertise on the IL-2R to address these issues and better understand mechanistically the basis by which IL-2R signaling regulates Treg homeostasis and promotes susceptibility to autoimmunity. The following aims are proposed: 1) To establish the gene signatures for peripheral Treg subsets that depend on IL-2R, STAT5 and mTORC1 signaling; 2) To determine the relative roles of IL-2R, STAT5 and mTORC1 signaling for survival and metabolic function, including the contribution of lipid biosynthesis and Bcl-2, for the homeostasis of peripheral Treg subsets; 3) To define the extent absent IL-2R, STAT5, and mTORC1 signaling alters Treg function and to determine the cellular and molecular basis by which reduced, not absent, IL-2R signaling in Tregs promotes autoimmunity in NOD mice.


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 = $600,832 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	5	11/8/2024	NON-COMPETING CONTINUATION	$600,832
														Subtotal = $600,832

Issue Date FY: 2024 ( Subtotal = $619,414 )
2024	2024	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	4	11/15/2023	NON-COMPETING CONTINUATION	$557,472
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	001	4	5/16/2024	NON-COMPETING CONTINUATION	$61,942
														Subtotal = $619,414

Issue Date FY: 2023 ( Subtotal = $619,414 )
2023	2023	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	3	12/1/2022	NON-COMPETING CONTINUATION	$619,414
														Subtotal = $619,414

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	2	11/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $619,414 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	2	11/17/2020	NON-COMPETING CONTINUATION	$619,414
														Subtotal = $619,414

Issue Date FY: 2020 ( Subtotal = $619,414 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	000	1	12/10/2019	NEW	$619,414
														Subtotal = $619,414

Grand Total All Awards = $3,078,488

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IL-2R-dependent mechanisms in regulation of Treg homeostasis and autoimmunity

Award Number: R01AI148675

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: 12/10/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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